What’s New in VTE? Why Old Rules May No Longer Apply

Thirty years ago, venous thromboembolism (VTE) wasn’t a recondite disease. It is now, because the VTE research community has more aura than a migraine. No farming needed. If there’s a clinical question that’s crossed your mind while making a VTE-related decision, they’ve produced a study to answer it. They’ve even published studies that answer questions you didn’t know you had. Their brilliance and output come at a price though — you’ve got to keep up.Why ‘Provoked’ Isn’t the End of the Story Perhaps the most significant paradigm change over the past two decades is the shift from categorical, fixed treatment durations to individualized calculation of recurrence risk. The provoked vs unprovoked dichotomy is now an anachronism, much like punting on fourth and short. The same goes for fixed durations, or doses, of anticoagulation. Over the past year, we’ve learned more about both practices.First, a single center, randomized controlled trial (RCT) published in The New England Journal of Medicine in 2025 reported a significant reduction in VTE with extended anticoagulation after a provoked VTE. The authors purposely enrolled patients with at least one enduring risk factor to simulate a clinical scenario that’s commonly encountered but rarely studied. They also included patients with both major and minor provoking factors. While the risk benefit margin for extending anticoagulation after a minor provoking factor is thinner than a surgeon’s differential, an increased rate of recurrence is expected. The treatment group received an extra year of low dose apixaban (2.5 mg twice daily) after the initial 3 months of treatment. They had a dramatic reduction in recurrence, largely due to the inflated, 10% recurrence rate in the placebo group. One could argue, as the accompanying editorial does, that the study result was predetermined by the inclusion criteria. Fair enough, but the authors did a really nice job demonstrating you can’t label an event “provoked” and stop there.Extended Anticoagulation: Full Dose or Half Dose? The half (or low) dose of apixaban chosen for the intervention group leads us to two more important trials published in 2025: RENOVE and API-CAT. Both were designed to test whether extending anticoagulation beyond 6 months should be done using full treatment vs half dosing. Past data from the AMPLIFY-EXT and EINSTEIN CHOICE RCTs suggested reduced dose apixaban and rivaroxaban respectively were comparable to treatment doses when choosing to extend anticoagulation beyond 6 months. Three quarters of the patients in AMPLIFY-EXT and EINSTEIN-CHOICE had been diagnosed with unprovoked VTE, while less than 3% had malignancy. Guidelines have been noncommittal on reduced dosing for extended treatment, using words like “suggest” or “consider.” In accordance with the populations enrolled in AMPLIFY-EXT and EINSTEIN CHOICE, I’d adopted it for unprovoked (not malignancy-associated) VTE.RENOVE vs API-CAT: Two Trials, Two Verdicts There were important differences between RENOVE and API-CAT. The former enrolled patients with unprovoked and recurrent VTE, while those in the latter trial had malignancy-associated VTE. Both were powered to prove noninferiority for recurrent event rates, with the former using the upper bound of the hazard ratio and the latter the rate itself. RENOVE was the longer trial and both apixaban and rivaroxaban were used, while apixaban was studied in API-CAT. The differences don’t stop there, but for brevity’s sake my discussion of them does.The short take is that RENOVE was negative and API-CAT was positive. Said another way, RENOVE was unable to establish noninferiority for recurrence, but API-CAT was. The bleeding reduction signal was stronger in RENOVE than in API-CAT, possibly due to the longer follow-up period, and patients on reduced dosing had greater net clinical benefit in RENOVE. Unfortunately, RENOVE’s hierarchal design dictated that the absence of noninferiority for the primary outcome (recurrence) made it a negative trial. Because our “Bayesian priors” favored reduced dosing, it’s easy to find reassurance in both RENOVE and API-CAT.The Bottom Line In summary, seeing the world through a provoked vs unprovoked lens is overly reductionist. Half, or low dosing, for extended anticoagulation is important for optimizing risk-benefit. VTE treatment paradigms continue to evolve, and they’re not getting easier. You better keep up. Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington, DC. He covers a wide range of topics in pulmonary, critical care, and sleep medicine.