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.