Comparisons of Basic Characteristics and Outcomes between Eligible and Ineligible Patients
We found that the risk of major bleeding, stroke and systemic embolism, and all-cause death in ineligible patients with CHADS2score ≥2 was significantly higher than those in eligible patients. The poor prognosis of these ineligible patients may be explained by more comorbidities such as anaemia, heart failure, coronary artery disease, renal insufficiency, liver disease, or more concomitant medications such as antiplatelet agents or NSAIDs than those in eligible patients. Therefore, ineligibility for Phase III trials can be considered a variable summarising these factors and indicating worse outcomes.
Furthermore, all our patients were prescribed anticoagulants by their physicians, regardless of their eligibility for Phase III trials of DOACs. However, the outcomes of eligible and ineligible patients differed markedly, suggesting that the risks and benefits of anticoagulant therapy depend on patient eligibility. Our results showed that not only is the risk of stroke not sufficiently reduced by anticoagulation in ineligible patients, but the risk of major bleeding is almost double that of eligible patients, probably due to over-anticoagulation. Notably, some might assume that ineligible patients have a higher risk of stroke and that the benefit of anticoagulant treatment is greater; however, this is not the case, and our results suggest that the risk of bleeding with anticoagulation outweighs the benefit of stroke prevention in ineligible patients owing to various factors mentioned above. Patients who were deemed ineligible because of a low CHADS2 score and were excluded from the outcome comparison had a low absolute risk of stroke, and the expected absolute risk reduction with anticoagulant therapy was small; therefore, the risk of bleeding was relatively high, making anticoagulants less advisable. The guidelines also state that anticoagulation is recommended for patients with NVAF and a CHADS2 score of 1 or higher. Finally, the similar efficacy and safety demonstrated in Phase III trials of DOACs may be unlikely in ineligible patients.
As suggested by the ELDERCARE-AF study,19 which included inappropriate elderly patients for oral anticoagulants at approved doses or recommended strengths for reasons such as decreased eGFR and chronic use of NSAIDs, lower doses of DOACs might be a solution to prevent major bleeding if lower doses successfully reduce the risk of stroke compared to no anticoagulation. However, the risk of major and clinically relevant minor bleeding remained significantly higher in patients who received a lower dose of edoxaban than in those who received a placebo in the ELDERCARE-AF study.19
Our retrospective cohort study has certain limitations that are distinctive to this type of study. The data used in this cohort were initially obtained from medical records and were not collected according to a study protocol. Furthermore, the study had a notable amount of missing data, particularly regarding relevant confounding factors, and many patients were lost to follow-up.
The criteria developed from the four trials are generally considered valid; however, it is essential to note that we were unable to assess specific exclusion criteria, such as patients who were planning to undergo ablation or major surgery or those with a life expectancy of less than one year at the time of enrollment. In addition, all patients within the cohort were receiving warfarin at the time of enrollment, and some transitioned to direct oral anticoagulants (DOACs). The effects of such transitions on outcomes and their potential relationship with eligibility at enrollment were not evaluated.
Approximately half the real-world patients with NVAF on anticoagulants are ineligible for Phase III trials of DOACs. In particular, those with a high risk of stroke had significantly worse outcomes than eligible patients; that is, they had a higher risk of stroke and major bleeding and death. The benefits of DOACs presented in Phase III trials may not necessarily apply to the patients ineligible for such trials. This gap between evidence and practice20 is an issue for anticoagulants’ real-world safety and efficacy.