Lower International Normalized Ratio Anticoagulation in Patients with Mechanical Valves Needs Robust Evaluation

To the Editor, We read with great interest the SWEDEHEART analysis1 by Lu et al evaluating long-term outcomes after mechanical aortic valve replacement. This large, nationwide registry-based study provides real-world data on bleeding and thromboembolic complications in contemporary practice, both of which are influenced by international normalized ratio (INR) targets. At 8 years, patients with an On-X prosthesis experienced cumulative incidences of 7.2% for major bleeding and 7.3% for thromboembolic events versus 7.0% and 6.4% for patients with other mechanical valves. Importantly, these outcomes did not differ meaningfully between On-X and other bileaflet prostheses, challenging the assumption that On-X valves’ design confers distinctive protection against thrombosis. These event rates underscore the persistent risks associated with lifelong anticoagulation in patients with mechanical valves. Guideline recommendations have evolved in response to the PROACT trial.2 This trial showed that reduced-intensity warfarin (INR 1.5-2.0) plus aspirin was noninferior to standard therapy in patients with On-X aortic valves, with fewer bleeding events. On this basis, the 2017 ACC/AHA focused update introduced a Class IIb option for a lower INR in On-X aortic valves without additional risk factors, and in 2020, the full guideline formalized this recommendation with clearer parameters, including initiation 3 months post-surgery with concomitant aspirin. However, Lu et al’s findings suggest that similar outcomes may be expected across different models of bileaflet prostheses. They added that use of the lower INR target for On-X valves may have been inconsistent in routine care, and INR data were not available to assess adherence. The LOWERING-IT trial further suggested that the benefits of reduced-intensity anticoagulation are not confined to On-X valves.3 In 396 low-risk patients with non-On-X bileaflet aortic valves, targeting INR 1.5-2.5 was noninferior to 2.0-3.0 for thromboembolism and significantly reduced bleeding over more than 2,000 patient-years of follow-up. Despite these findings, current recommendations remain based on small trials and historical cohorts. In an international survey, we found that most clinicians recognized these limitations and were willing to randomize their patients to lower INR strategies.4 What is now required is a large, rigorously designed randomized trial, and the LIMIT trial (NCT03636295) has been developed to provide this evidence.5 LIMIT is a multicentre, randomized, prospective open-label blinded-end-point trial that will enroll 2,625 patients with bileaflet aortic valves worldwide. Eligible participants must be at least 3 months post-surgery and are randomized 1:1 to a low INR target (1.5-2.5) or to current guideline-recommended ranges. With sequential primary outcomes of noninferiority for thromboembolism and superiority for major bleeding, LIMIT is positioned to determine whether reduced-intensity anticoagulation can be safely extended beyond On-X valves. As of September 24, 2025, 869 patients have been enrolled in LIMIT. With an event-driven approach, LIMIT will definitively establish whether a unified, lower INR strategy for all bileaflet prostheses can reduce lifelong bleeding complications while preserving protection against thromboembolic events. None declared. Drs. Belley-Cote and Whitlock are the principal investigators of the LIMIT trial. They have received grant funding from Abbott. Dr. Belley-Cote has received consulting fees from Trimedic Therapeutics and Abbott Laboratories. Dr. Whitlock has received grant funding from Boston-Scientific, Bayer, Roche and Atricure. He also received consulting fees from Johnson&Johnson, Medtronic and Atricure.

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