The patient’s perspective increasingly influences the choice of prosthesis, particularly considering the perceived quality of life associated with antiplatelet/anticoagulant medication. Added to this is the recent rise of percutaneous interventions as potential solutions for structural degeneration in bioprostheses, which has led to a significant decline in the recommendation for mechanical prostheses, even in younger populations. 

However, mechanical aortic prostheses continue to hold a crucial role with well-defined indications for aortic stenosis treatment, with ongoing advancements in their technological development. This study aims to support the indication proposed in the PROACT (Prospective Randomized On-X Anticoagulation Clinical Trial) study, where a low INR in the context of an On-X® aortic valve implant could be considered safe for thromboembolic events, with a reduced risk of bleeding complications. 

It is known that all mechanical aortic prostheses require lifelong oral anticoagulation with a vitamin K antagonist, and that other studies examining alternative antithrombotics (dual antiplatelet therapy, dabigatran, or apixaban) have not been considered safe for thromboembolic events. 

Following the PROACT study, which confirmed the efficacy of a combination of low-dose warfarin (INR between 1.5 and 2) and low-dose aspirin (ASA) after the first three postoperative months in high thrombotic risk patients with home INR monitoring, the FDA required an additional study to confirm this hypothesis, enabling this indication for all patients with an On-X® prosthesis in the aortic position regardless of thrombotic risk or monitoring method. 

The study analyzed here is a prospective, observational, multicenter study that followed a cohort of up to 510 patients over five years. They received low-dose warfarin combined with low-dose ASA (if no contraindications existed) after three months of standard-dose anticoagulation following the prosthetic implant. Patients included were over 18 years old with a life expectancy exceeding five years, excluding any patients with another prosthetic valve implant other than aortic. The control group was randomly selected from the PROACT study and included all patients who received standard-dose warfarin to maintain an INR between 2 and 3, along with low-dose ASA regardless of thrombotic risk. The primary variable studied was the incidence of thromboembolic events, valve thrombosis, or major bleeding, analyzed in four subgroups: home vs. clinic-based INR monitoring and high vs. low thrombotic risk. Secondary variables included the occurrence of these events individually, overall thrombotic events, death rate, reoperations, or prosthesis explants, as well as general bleeding (both major and minor). Follow-up consisted of two visits in the first postoperative year and an annual visit for the next four years. This article includes data up to the one-year follow-up for all patients, with final results expected in 2027. A 95% confidence interval was used, with primary variable incidence studied using Poisson regression and the Kaplan-Meier curve for the percentage of patients free from the composite primary endpoint. 

Among the 510 patients studied, 128 (25.1%) were at high thrombotic risk, while 382 (74.9%) were at low risk. Of these, 70 (13.7%) had home INR monitoring, and 440 (86.2%) clinic-based. The median follow-up was 3.35 years (1,562.9 patient-years), with a median INR of 1.9. 

For the primary endpoint, the total incidence of thromboembolism, valve thrombosis, or major bleeding was 2.3% per patient-year, significantly lower than the 5.4% per patient-year in the control group (95% CI 4.1-6.9%). In subgroup analysis, the primary endpoint incidence was 2.4% in home-monitored patients and 2.3% in clinic-monitored patients, notably lower than the 5.4% in the control group. For thrombotic risk categories, high-risk patients had a 2.5% incidence, and low-risk patients a 2.2%, compared to 5.8% and 4% in the control groups, respectively. Subgroup analysis showed statistically significant results for high-risk patients but not for low-risk patients. The Kaplan-Meier curve estimated that at least 89.7% of patients would be free of any primary event over five years, with statistical significance. 

Secondary analyses revealed significantly fewer major bleeds in the study group than in the control group (0.6% per patient-year vs. 3.8% per patient-year). Incidences of thromboembolic events and valve thrombosis were low and similar between groups. The overall bleeding rate, including minor bleeds, was also significantly lower in the study group (1.9% vs. 7.1%). 

COMMENTARY: 

The article confirms, up to the current follow-up, the findings of the PROACT study, suggesting that a lower INR with low-dose ASA is safe for preventing thromboembolic events and reduces bleeding complications in patients with On-X® valves in the aortic position. The FDA requested this study to validate this hypothesis in real-world patients with these valves, regardless of monitoring method or thrombotic risk. 

The results, which even improve upon those of the PROACT study, support the practice of reducing anticoagulation in On-X® aortic valve patients. However, therapeutic approaches should continue to be individualized. 

Despite these findings, final results will be available in 2027 after five years of follow-up, as designed. 

REFERENCE: 

Oo AY, Loubani M, Gerdisch MW, Zacharias J, Tsang GM, Perchinsky MJ, et al. On-X aortic valve replacement patients treated with low-dose warfarin and low-dose aspirin. Eur J Cardiothorac Surg. 2024 May 3;65(5):ezae117. doi: 10.1093/ejcts/ezae117.