Patients with congenital heart disease (CHD) are at higher risk of coagulation disorders than general population [1]. Nevertheless, being born with a CHD includes the possibility to experience atrial arrhythmias (AA) or interventions which may require anticoagulation therapy during lifespan. The mismatch between the lack of robust data and the need to treat adults with CHD (ACHD) has compelled clinicians to approach oral anticoagulation therapy as a leap of faith amidst uncertain evidence. Although the stroke and pulmonary embolism prevention has traditionally been managed with vitamin K antagonists (VKA), it has been found that CHD patients spend only less than 42% of their time with international normalized ratio (INR) levels in the therapeutic range [2]. Non-vitamin K antagonist oral anticoagulants (NOACs) offer an alternative to VKAs, with a lower risk of bleeding in non-CHD patients, fewer dietary and drug interactions, and the possibility of avoiding the INR monitoring. While the initial observations of NOACs application in ACHD presented by the prospective worldwide NOTE registry were promising, they were subsequently contradicted by larger data from a retrospective nationwide study, which revealed increased rates of adverse events related to NOACs compared to VKAs [3,4]. The PROTECT-AR study (Prospective Study on the Safety and Effectiveness of Apixaban for the Prevention of Thromboembolism in Adults with Congenital Heart Disease and Atrial Arrhythmias) recently published by A. Kartas et al., was designed as a prospective, multicentre, non-interventional cohort study on the use of a single NOAC for the prevention of thromboembolism in ACHD patients with AA. The study included a total of 218 ACHD patients aged more than 17 years old (mean age 51 years, 45.9% males) treated with apixaban and followed-up for a median of 2.8 years. Of these, 73 individuals who had received VKAs before transitioning to apixaban served as the historical control group. Compared to VKAs, the use of apixaban was shown to be non-inferior in terms of the primary effectiveness endpoint (annualized rate of stroke or thromboembolism 0.6% vs. 1.8%, P non-inferiority < 0.001) and to improve quality of life. The annualized rate of major bleeding was 1.5% in the apixaban group and 2.4% in the VKA group (p = 0.48), indicating similar safety. The study by Kartas et al. therefore confirmed the relatively low rates of thromboembolism and major bleeding for apixaban that were previously observed in the NOTE registry, which included all currently available NOACs. The PROTECT-AR study also provided a certain reassurance regarding apixaban use in patients with CHD of severe complexity, as none of the major thromboembolic events and only one out of eight major bleeding events occurred in this subset of patients. However, this incidence may be underestimated since this group was the least represented in the sample population (26.1%). The study had in fact several limitations, including not being a randomized and adequately powered trial, and the inability to investigate factors associated with event occurrence.
Most interestingly, the study prompts a fundamental inquiry into the appropriateness of employing a bleeding score validated for the general population to evaluate the true bleeding risks of ACHD patients. In fact, only one out of the eight major bleeding episodes in the apixaban group occurred in patients with a HASBLED score ≥ 3. Do the bleeding events recorded in the study accurately portray the safety profile of NOACs, or are they instead indicative of an improper assessment of bleeding risk among ACHD patients? Further research is needed to delve into this matter and reinforce the evidence on the efficacy and safety of NOACs in the ACHD population.
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