SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.
Clinically, VTE is classified as provoked, occurring after transient risk factors such as surgery, trauma, or immobility, or unprovoked, when no clear trigger is identified. Standard management involves 3 months of anticoagulation for provoked events and extended therapy for unprovoked events because of their higher recurrence risk (6–10% per year after discontinuation). However, many patients present with provoked VTE in the context of enduring risk factors such as obesity, chronic inflammatory disease, atherosclerotic cardiovascular disease or chronic pulmonary conditions, factors that may sustain a prothrombotic milieu even after the transient trigger has resolved. Current guidelines offer limited direction for this increasingly common patient subset.
Study Rationale and Design
The Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism (HI-PRO) trial sought to clarify whether continued low-intensity anticoagulation could safely reduce recurrence risk in such patients. This single-center, double-blind, randomized study enrolled 600 adults who had completed at least 3 months of standard anticoagulation for a provoked VTE and who also had at least one enduring risk factor for recurrence. Participants were randomized 1:1 to receive Apixaban (ELIQUIS®) 2.5 mg twice daily or placebo for 12 months.
Enduring risk factors included obesity (BMI ≥30), chronic lung disease, autoimmune or inflammatory disorders, and atherosclerotic cardiovascular disease (limited to ≤35% of patients per arm to control for aspirin use). Eligible VTE events included deep vein thrombosis, pulmonary embolism (including isolated subsegmental PE), or both.
The Primary efficacy endpoint was symptomatic recurrent VTE by day 365. The Primary safety endpoint was major bleeding per International Society on Thrombosis and Haemostasis (ISTH) criteria.
Results
The study population had a mean age of 59.5 years, 57% were women, and 19% were non-White.
By 12 months, symptomatic recurrent VTE occurred in 1.3% of patients receiving Apixaban versus 10.0% of those receiving placebo (Hazard Ratio [HR] 0.13; 95% CI, 0.04–0.36; P<0.001), representing an 87% relative risk reduction. The composite cardiovascular outcome, including cardiovascular death, nonfatal myocardial infarction, stroke, or limb ischemic events, was infrequent and comparable between groups (0.7% vs. 1.0%).
Major bleeding was rare, occurring in one patient (0.3%) in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding occurred more often with Apixaban (4.8% vs. 1.7%; HR 2.68; 95% CI, 0.96–7.43; P=0.06), with vaginal, hematuric, and rectal bleeding being the most common types. Nonfatal adverse events were balanced between arms.
Medication adherence was high throughout the study, and no deaths were attributed to bleeding or cardiovascular causes.
Interpretation
Extended-duration, low-intensity Apixaban provided robust protection against recurrent VTE in patients with provoked events and ongoing risk factors, an underrepresented and clinically relevant population. The recurrence rate in the placebo group (10% at 1 year) underscores that the conventional dichotomy of provoked versus unprovoked VTE may oversimplify recurrence risk. Patients with enduring prothrombotic conditions appear to have recurrence risks comparable to those with unprovoked events.
The low incidence of major bleeding supports the safety of this approach, though the modest increase in nonmajor bleeding emphasizes the need for individualized risk–benefit assessment, especially in those also receiving antiplatelet therapy.
Clinical Implications
The HI-PRO findings challenge the traditional framework that limits extended anticoagulation to unprovoked VTE and cancer-associated thrombosis. Instead, they highlight that patients with provoked VTE but persistent risk factors, such as chronic inflammatory states, cardiometabolic disease, or obesity, may benefit from continued low-intensity anticoagulation beyond the initial 3-month course.
Incorporating enduring risk factors into recurrence-risk models and treatment algorithms could help refine long-term management. Emerging approaches such as VTE-PREDICT scoring, polygenic risk assessment, and AI-driven modeling may further individualize these decisions.
Takeaway
Among patients with provoked VTE and ongoing risk factors, 12 months of low-dose Apixaban therapy significantly reduced recurrent VTE with a favorable safety profile. The HI-PRO trial supports a more nuanced, risk-adapted approach to secondary prevention, where the duration and intensity of anticoagulation are guided not solely by the event’s provoked or unprovoked status, but by the persistence of underlying prothrombotic conditions.
Apixaban for Extended Treatment of Provoked Venous Thromboembolism. Piazza G, Bikdeli B, Pandey AK, et al. for the HI-PRO Trial Investigators. N Engl J Med 2025;393:1166-1176.
