\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,polish,english]{babel}
\usepackage{CJKutf8}



\usepackage{float}








\begin{document}

\title{Outcomes of real-world patients with non-valvular atrial fibrillation on
anticoagulants ineligible for Phase III trials of direct oral
anticoagulants}



\author[1]{Mayumi Higa}%
\author[2]{Takeshi Morinoto}%
\author[3]{Masayuki Ikeda}%
\author[4]{Shinichiro Ueda}%
\affil[1]{University of the Ryukyus Faculty of Medicine Graduate School of Medicine}%
\affil[2]{Hyogo College of Medicine}%
\affil[3]{Kagawa University Faculty of Medicine Graduate School of Medicine}%
\affil[4]{University of the Ryukyus}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Aims: To compare the outcomes of real-world Japanese patients with
nonvalvular atrial fibrillation who are ineligible for phase III trials
of direct oral anticoagulants with those of eligible patients. Methods:
In retrospective cohort design, consecutively registered patients with
nonvalvular atrial fibrillation who had taken warfarin were followed up
and assessed eligibility of patients for phase III trials of direct oral
anticoagulants. The effects of the ineligibility of patients on outcomes
were estimated using Cox proportional hazards models to calculate the
hazard ratio (HR) and 95\% confidence interval. Results: We registered
7826 Japanese patients with nonvalvular atrial fibrillation from 71
hospitals. Nearly half (48.2\%, n=3772) of these patients were
ineligible for phase III trials of direct oral anticoagulants, mainly
because of low CHADS2 scores (26.4\%), renal dysfunction (9.5\%), anemia
(6.4\%), and chronic treatment with nonsteroidal anti-inflammatories
(4.0\%). After excluding patients with a CHADS2 score \textless{}2
(n=2064, 26.4\%) from total ineligible patients, the remaining
ineligible patients (n=1708) exhibited significantly greater risks of
major bleeding (unadjusted hazard ratio 2.00, 95\% confidence interval
1.63--2.44, p\textless{}0.0001), stroke/systemic embolism (unadjusted
hazard ratio 1.53, 95\% confidence interval 1.17--1.98, p=0.0016), and
all-cause mortality (unadjusted hazard ratio 2.84, 95\% confidence
interval 2.36--3.43, p\textless{}0.0001) compared to the eligible
patients. Conclusions: The benefits and risks of direct oral
anticoagulants suggested by phase III trials may not necessarily apply
to patients ineligible for Phase III trials. This gap between evidence
and practice is an issue in the real-world safety and efficacy of
anticoagulants.%
\end{abstract}%



\sloppy


Outcomes of real-world patients with non-valvular atrial fibrillation on
anticoagulants ineligible for Phase III trials of direct oral
anticoagulants

Running title: Real-world patients with NVAF

Mayumi Higa\textsuperscript{1}, Takeshi Morimoto\textsuperscript{2},
Masayuki Ikeda\textsuperscript{3}, Shinichiro
Ueda\textsuperscript{1,4,5}

\textsuperscript{1}Department of Clinical Research and Management,
University of the Ryukyus Graduate School of Medicine, Okinawa, Japan.

\textsuperscript{2}Department of Clinical Epidemiology, Hyogo Medical
University, Hyogo, Japan.

\textsuperscript{3} Department of Medical Informatics, Kagawa University
School of Medicine, Kagawa, Japan.

\textsuperscript{4} Department of Clinical Pharmacology \& Therapeutics,
University of the Ryukyus Graduate School of Medicine, Okinawa, Japan.

\textsuperscript{5} Department of Health Data Science, Yokohama City
University Graduate School of Data Science, Yokohama, Japan

Correspondence:

Dr Shinichiro Ueda, Department of Clinical Pharmacology \& Therapeutics,

University of the Ryukyus Graduate School of Medicine, Okinawa, 903-0215
Japan

Email:\emph{blessyou@med.u-ryukyu.ac.jp}

ORCID ID https://orcid.org/0000-0001-8133-9361

Phone: +81-98-895-1195

The authors confirm that the Principal Investigator for this paper is Dr
Shinichiro Ueda and that he had direct clinical responsibility for
patients.

Keywords: non-valvular atrial fibrillation, anticoagulation, Phase III
trial, eligibility

Word count: 2469

Table count: 5

Figure count: 2

\textbf{Key Points}

\textbf{What is already known about this subject}

\begin{itemize}
\tightlist
\item
  Phase III trials for regulatory approval typically have conducted
  under strict eligibility criteria that exclude certain patients.
\item
  These ineligible patients often receive the approved drugs post-trial.
\item
  The balance of risks and benefits for these ineligible patients
  remains unclear.
\end{itemize}

\textbf{What this study adds}

Patients ineligible for Phase III trials of direct oral anticoagulants,
yet receiving anticoagulants for non-valvular atrial fibrillation,
exhibited worse outcomes compared to eligible patients.

The study points to a potential discrepancy between clinical evidence
and real-world practice regarding the safety and effectiveness of
anticoagulants.



\textbf{ABSTRACT}

\textbf{Aim:} To compare the outcomes of real-world Japanese patients
with nonvalvular atrial fibrillation who are ineligible for Phase III
trials of direct oral anticoagulants with those of eligible patients.

\textbf{Methods:} In retrospective cohort design, consecutively
registered patients with nonvalvular atrial fibrillation who had taken
warfarin were followed up and assessed patients' eligibility for Phase
III trials of direct oral anticoagulants. The effects of the
ineligibility of patients on outcomes were estimated using Cox
proportional hazards models to calculate the hazard ratio (HR) and 95\%
confidence interval.

\textbf{Results:} We registered 7826 Japanese patients with nonvalvular
atrial fibrillation from 71 hospitals. Approximately half (48.2\%,
n=3772) of these patients were ineligible for Phase III trials of direct
oral anticoagulants, mainly because of low CHADS\textsubscript{2}scores
(26.4\%), renal dysfunction (9.5\%), anaemia (6.4\%), and chronic
treatment with nonsteroidal anti-inflammatories (4.0\%). After excluding
patients with a CHADS\textsubscript{2} score \textless{}2 (n=2064,
26.4\%) from total ineligible patients, the remaining ineligible
patients (n=1708) exhibited significantly greater risks of major
bleeding (unadjusted hazard ratio 2.00, 95\% confidence interval
1.63--2.44, \emph{p} \textless{}0.0001), stroke/systemic embolism
(unadjusted hazard ratio 1.53, 95\% confidence interval
1.17--1.98,\emph{p} =0.0016), and all-cause mortality (unadjusted hazard
ratio 2.84, 95\% confidence interval 2.36--3.43, \emph{p}
\textless{}0.0001) compared to the eligible patients.

\textbf{Conclusion:} The benefits and risks of direct oral
anticoagulants suggested by Phase III trials may not necessarily apply
to patients ineligible for Phase III trials. This gap between evidence
and practice is an issue in anticoagulants' real-world safety and
efficacy.



\textbf{I. Introduction}

Direct oral anticoagulants (DOACs) have been increasingly prescribed to
patients with non-valvular atrial fibrillation (NVAF) following
regulatory approval and guideline recommendations following successful
Phase III trials demonstrating their non-inferiority and superiority to
warfarin.\textsuperscript{1-5} However, the results from pivotal trials
should be interpreted with caution because of the strict inclusion and
exclusion criteria to ensure participant safety and provide clear
results for regulatory approval. The Food and Drug Administration
recommends that enrolling participants with a wide range of baseline
characteristics may create a trial population that more accurately
reflects the patients who are likely to take the drug if it is approved
and may allow evaluation of the impact of these characteristics on the
trial drug's safety and efficacy.\textsuperscript{6} The ICH Steering
Committee has also stated that as drug development progresses, the study
population should be expanded to reflect the target
population.\textsuperscript{7}

These recommendations aim to ensure that the results of Phase III trials
can be used for a broader range of patients; however, several studies
have attempted to assess the generalizability of the results from Phase
III trials of DOACs to the extent to which real-world patients with NVAF
can be enrolled in Phase III trials. The proportion of real-world
patients eligible for the trials varied widely, ranging from 35\% to
72\%.\textsuperscript{8-13} There were trends towards low eligibility
for ROCKET-AF and high eligibility for ARISTOTLE and RE-LY, presumably
because of the CHADS\textsubscript{2} score as an inclusion criterion.
However, there have been few comparisons of outcomes between eligible
and ineligible patients in Phase III trials. This study aimed to
determine the proportion of real-world Japanese patients with NVAF
eligible for Phase III trials and compare the characteristics and
outcomes of ineligible and eligible patients.

\textbf{II. Methods}

\textbf{Study design}

We conducted a historical registry study of patients with NVAF taking
warfarin at 71 centres in Japan. We registered patients in Japan on
February 26, 2013, and followed them until February 25, 2017.

\textbf{Ethics}

The ethics committees of all 71 participating centres approved the study
following the Ethical Guidelines for Medical and Health Research
Involving Human Subjects in Japan. The requirement for individual
written informed consent was waived.

\textbf{Patients}

Consecutive patients with NVAF who had already received warfarin on
February 26, 2013, were retrospectively registered. Patients with
mechanical heart valves and previous pulmonary or deep vein thrombosis
diagnoses were excluded from the study.

\textbf{Data Collection and Definitions}

Trained clinical research coordinators reviewed and collected relevant
clinical information, including patient characteristics, laboratory
data, risk of ischemic stroke (CHADS\textsubscript{2} score), and major
bleeding (HAS-BLED score) at baseline and relevant medications directly
from medical charts at baseline and at 1, 2, 3, and 4 years of
follow-up. Definitions of the baseline characteristics have been
previously described.\textsuperscript{14} The
CHADS\textsubscript{2}score was developed to estimate the stroke risk in
patients with NVAF,\textsuperscript{15} and the HAS-BLED score was
developed to predict major bleeding in patients receiving
anticoagulation therapy.\textsuperscript{16}

\textbf{Assessment of our registered patients' eligibility for Phase III
trials of DOACs}

We scrutinised the most frequently used inclusion and exclusion criteria
of the four DOACs Phase III trials (Table
1).\textsuperscript{1,2,4,5}Baseline data collected at registration for
all patients (medical history, background, and laboratory values) were
checked against the developed inclusion and exclusion criteria to assess
eligibility. Regarding the CHADS2 score, two trials used [?]2 as a
criterion, and the others used [?]1. We used [?]2 as our criterion.
Therefore, ineligible patients included those with a
CHADS\textsubscript{2} score of \textless{}2. In addition, we checked
the baseline data against each Phase III trial's inclusion and exclusion
criteria.

\textbf{Comparison of outcomes between eligible and ineligible patients
with CHADS\textsubscript{2} score [?]2}

We compared the outcomes between eligible and ineligible patients after
excluding patients with a CHADS\textsubscript{2} score of \textless{}2.
A comparison between eligible and ineligible patients, including those
with a CHADS\textsubscript{2} score of \textless{}2, was also performed
for sensitivity analysis.

\textbf{Outcome measure}

The primary outcome was major bleeding. Major bleeding was defined
following the International Society on Thrombosis and Hemostasis
criteria.\textsuperscript{17,18} Other outcomes were stroke, including
transient ischemic attack, systemic embolism (Stroke/SE), and all-cause
mortality.

\textbf{Statistical Analyses}

\textbf{Descriptive Statistics}

The eligibility proportions of all patients were described. The
proportion of patients who met each inclusion criterion and conflicted
with each exclusion criterion was described.

Clinical characteristics were described and compared between the
eligible and the ineligible patients with CHADS\textsubscript{2} scores
[?]2. Categorical variables were presented as numbers and percentages.
Continuous variables were expressed as means \selectlanguage{ngerman}± standard deviation (SDs),
median value, or interquartile range. The Student's t-test or Wilcoxon
rank-sum test was performed for continuous variables to evaluate
differences in characteristics between the two groups. The chi-square
test was used for categorical variables.

\textbf{Survival Analysis}

The incidence rates of outcomes are presented as cases per 100
patient-years. The cumulative incidence of outcomes was estimated using
the Kaplan--Meier method. The difference between eligible and ineligible
patients with CHADS\textsubscript{2} scores \selectlanguage{english}[?]2 was assessed using the
log-rank test. The effects of the ineligibility of patients on outcomes
were estimated using Cox proportional hazards models to calculate the
hazard ratio (HR) and 95\% confidence interval. Statistical significance
was set at \emph{P} \textless{}0.05 for all analyses. We presented only
unadjusted HR because the effects of ineligibility on the outcomes
reflected the integrated impact of many variables in ineligible
patients.

In addition, we added patients with CHADS\textsubscript{2} scores
\textless{}2 to the group of ineligible patients and compared them with
the eligible patients regarding baseline characteristics and outcomes as
part of the sensitivity analysis.

\textbf{III. Results}

We registered 7826 Japanese patients with NVAF and followed them for
four years; the median age was 74 (66--80) years old; 3755 (48.0\%)
patients were at least 75 years old, 2552 (33\%) were female; the mean
CHADS\textsubscript{2} score was 2.44.

\textbf{Eligibility of all registered patients}

Following our inclusion/exclusion criteria derived from Phase III trials
of DOACs (Table 1), 4054 (51.8\%) patients with NVAF were classified as
the eligible group, whereas the remaining patients (n=3772, 48.2\%) were
classified as the ineligible group mainly because of
CHADS\textsubscript{2} score \textless{}2 (26.4\%), renal dysfunction
(9.5\%), anaemia (6.4\%), and chronic treatment with nonsteroidal
anti-inflammatories (NSAIDs (4.0\%) (\textbf{Table 2}
).\textsuperscript{14}

\selectlanguage{english}\textbf{Comparisons of Baseline Characteristics between Eligible and
Ineligible Patients with CHADS\textsubscript{2} Score [?]2}

\textbf{Figure 1} presents the flow diagram of the study. We excluded
patients with CHADS\textsubscript{2} \textless{}2 (n=2063, 26.4\% of all
registered patients) from comparing outcomes. \textbf{Table 3} presents
the baseline characteristics of the eligible and ineligible patients
with CHADS\textsubscript{2} \selectlanguage{english}[?]2. Ineligible patients were more likely to
be elderly, female, and have comorbidities such as stroke, heart
failure, coronary artery disease, chronic liver disease, and kidney
disease than the eligible patients. The CHADS\textsubscript{2} score
after excluding patients with \textless{}2 and the HAS-BLED score were
significantly higher in ineligible patients than in eligible patients.

\selectlanguage{english}\textbf{Comparisons of Outcomes between Eligible and Ineligible Patients
with CHADS\textsubscript{2} Score[?]2}

At 4 years, 59\% of patients had completed follow-up, and the median
follow-up duration was 3.9 years. The cumulative incidence of major
bleeding at 4 years in the eligible and ineligible groups was 7.0\% and
13.4\%, respectively (\textbf{Figure 2a} ). The risk of major bleeding
in ineligible patients with CHADS\textsubscript{2} score \selectlanguage{english}[?]2 was almost
double that of eligible patients and statistically significantly higher
(\textbf{Table 4} ). The 4-year cumulative stroke and systemic embolism
incidence in the eligible and ineligible groups was 5.5\% and 7.5\%,
respectively (\textbf{Figure 2b} ). Notably, both groups had a
CHADS\textsubscript{2} score of \selectlanguage{english}[?]2; however, the risk of stroke/SE was
significantly higher in ineligible patients than in eligible patients
(\textbf{Table 4} ). At 4 years, the cumulative incidence of death from
any cause in the eligible and ineligible groups was 7.3\% and 17.6\%,
respectively (\textbf{Figure 1c} ). The risk of death from any cause in
ineligible patients was approximately three times higher than that in
eligible patients (\textbf{Table 4} ).

\textbf{Comparisons of Characteristics and Outcomes between Eligible and
Ineligible Patients, including those with CHADS\textsubscript{2} score
\textless{}2}

The baseline characteristics of eligible and ineligible patients,
including those with a CHADS\textsubscript{2} score \textless{}2, are
presented in \textbf{Table 5} . By putting low-risk patients back into
the ineligible group, it appears that there were more elderly patients
and patients with comorbidities in the eligible group, contrary to what
is shown in Table 3. Regarding outcomes, unlike the main analysis after
excluding patients with CHADS\textsubscript{2} score \textless{}2, there
was no difference in stroke/SE risk between the groups, and the effect
of ineligibility on the risk of major bleeding was smaller and did not
reach statistical significance, although the risk of all-cause mortality
remained significantly higher in ineligible patients with an unadjusted
HR (95\% CI) of 1.54 (1.29--1.83)\textbf{.}

\textbf{IV. Discussion}

Using a registry of Japanese patients with NVAF, we examined their
eligibility for Phase III trials comparing DOACs with warfarin.
Approximately 50\% of our ``real world'' registered patients with NVAF
were ineligible following the inclusion and exclusion criteria we
derived from reports of Phase III trials. Further comparative analysis
of outcomes strongly suggested that eligibility may affect the outcomes
in our patients, with significantly higher risks of major bleeding,
stroke/systemic embolism, and all-cause death in ineligible patients.

\textbf{Eligibility}

Our inclusion and exclusion criteria, which were derived from the most
commonly used criteria of four DOACs Phase III trials, were considered
valid for assessing eligibility and comparing outcomes between eligible
and ineligible patients because the proportion of eligible patients
using our criteria did not differ significantly from those using the
criteria of the individual Phase III trials (\textbf{Table S1} ).

Notably, several studies have reported the proportion of ``real-world''
patients with NVAF eligible for Phase III trials. In a UK general
practice database study,\textsuperscript{8} 68\% of patients would be
eligible for RE-LY, compared with 65\% and 51\% for ARISTOTLE and
ROCKET-AF, respectively. A retrospective cross-sectional database
analysis at the University Hospital Stroke Unit in
Belgium\textsuperscript{11} found that 47.6\% of patients were eligible
for RE-LY, 45.5\% for ARISTOTLE, and 39.3\% for ROCKET-AF. A study of
patients with a discharge diagnosis of AF in a large public hospital
network in Melbourne, Australia, showed that 60.5\%, 52.6\%, and 35.8\%
of patients would have been eligible for the ARISTOTLE, RE-LY, and
ROCKET-AF trials, respectively.\textsuperscript{12} Of the patients with
NVAF in the MAQI2 registry in Michigan, USA, 54.5\% would meet the
selection criteria used in RE-LY, 39.1\% for ROCKET-AF, and 59.9\% for
ARISTOTLE.\textsuperscript{13} The reported proportions of patients
eligible for Phase III trials of DOACs in real-world practice, including
our results, were consistently around 50\%, although there were some
differences among studies.

The ineligible patients were mainly characterised by low
CHADS\textsubscript{2} scores, renal dysfunction, anaemia, and chronic
NSAID use. The latter three are well-known risk factors for major
bleeding in patients with NVAF treated with anticoagulation. However,
elderly patients with these risk factors are often encountered in
real-world clinical practice, and anticoagulation should be considered
in the presence of atrial fibrillation. The studies cited above also
reported a high risk of bleeding, poor renal function, and concomitant
use of aspirin and antiplatelet agents as reasons for not enrolling in
the Phase III trial, despite taking anticoagulants in actual
practice.\textsuperscript{12,13}

\textbf{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
CHADS\textsubscript{2}score \selectlanguage{english}[?]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 CHADS\textsubscript{2} 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 CHADS\textsubscript{2} 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,\textsuperscript{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.\textsuperscript{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 practice\textsuperscript{20} is an issue for
anticoagulants' real-world safety and efficacy.

\textbf{Acknowledgements}

The authors are grateful to Ms. Kaori Une for her assistance with data
management; Ms. Yuko Fujita, Ms. Akane Kikuchi, Ms. Sayumi Mekaru, and
Ms. Hitomi Zukeran, all clinical research coordinators for data
collection from medical records; and Ms. Takako Okumura and Ms. Kayo
Chinen for study management. We are also indebted to the data managers
of the Institute for Clinical Effectiveness (Ms. Makiko Ohtorii, Ms. Ai
Sunagawa, Ms. Kaori Yamamoto, Ms. Sachiko Kitamura, Ms. Hirono Saito,
and Ms. Saeko Nagano) for the data management and statistical analyses.

\textbf{Author Contributions}

Mayumi Higa collected data from medical records, was involved in data
management, performed statistical analysis, and wrote the draft
manuscript. Takeshi Morimoto contributed to the study design, supervised
statistical analysis as the study biostatistician, and revised the draft
manuscript. Masayuki Ikeda contributed to the development of the study
concept and study design. Shinichiro Ueda conducted this registry study
as the principal investigator, contributed to the study concept and
design, and revised the draft manuscript.

\textbf{Conflict of interest}

Dr Shinichiro Ueda reports a research grant from Bristol Myers Squibb
and a lecturer's fee from Kowa. Dr Takeshi Morimoto reports lecturer's
fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan
Lifeline, Kowa, Toray, and Tsumura; manuscript fees from Bristol-Myers
Squibb and Kowa; advisory board for Novartis and Teijin.

\textbf{Funding Information}

This study was supported by a research grant from Bristol Myers Squibb
(CV185-401), which had no role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data;
preparation, review, or approval of the manuscript; and the decision to
submit the manuscript for publication.

\textbf{Data Access, Responsibility, and Analysis}

Dr Shinichiro Ueda had full access to all the data in the study and took
responsibility for the integrity of the data and the accuracy of the
data analysis.

\textbf{Data Availability statement}

Data in our registry will be available upon request after evaluating the
proposal based on scientific rationale and methodology, experience and
relevant qualifications of the research team, presence of a robust
statistical analysis plan, publication plan, and conflict of interests.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin
  in patients with atrial fibrillation \emph{N Engl J Med} .
  2009;\textbf{361} (12): 1139-1151. doi:10.1056/NEJMoa0905561
\item
  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in
  nonvalvular atrial fibrillation.~\emph{N Engl J Med} .
  2011;\textbf{365} (10): 883-891. doi:10.1056/NEJMoa1009638
\item
  Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in
  Japanese patients with atrial fibrillation -- the J-ROCKET AF study
  --.~\emph{Circ J} . 2012; \textbf{76} (9): 2104-2111.
  doi:10.1253/circj.cj-12-0454
\item
  Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin
  in patients with atrial fibrillation.~\emph{N Engl J Med} .
  2011;\textbf{365} (11): 981-992. doi:10.1056/NEJMoa1107039
\item
  Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in
  patients with atrial fibrillation.~\emph{N Engl J Med} .
  2013;\textbf{369} (22): 2093-2104. doi:10.1056/NEJMoa1310907
\item
  U.S. Department of Health and Human Services, Food and Drug
  Administration, Center for Drug Evaluation and Research, and Center
  for Biologics Evaluation and Research, Enhancing the diversity of
  clinical trial populations --- eligibility criteria, enrollment
  practices, and trial design guidance for industry, November 2020.
\item
  ICH Steering Committee, ICH harmonized tripartite guideline general
  considerations for clinical trials, 17 July 1997
\item
  Lee S, Monz BU, Clemens A, Brueckmann M, Lip GY. Representativeness of
  the dabigatran, apixaban and rivaroxaban clinical trial populations to
  real-world atrial fibrillation patients in the United Kingdom: a
  cross-sectional analysis using the General Practice Research
  Database.~\emph{BMJ Open} . 2012; \textbf{2} (6): e001768. Published
  2012 Dec 14. doi:10.1136/bmjopen-2012-001768
\item
  Yoon CH, Park YK, Kim SJ, et al. Eligibility and preference of new
  oral anticoagulants in patients with atrial fibrillation: comparison
  between patients with versus without stroke.~\emph{Stroke} .
  2014;\textbf{45} (10): 2983-2988. doi:10.1161/STROKEAHA.114.005599
\item
  Hagg L, Johansson C, Jansson JH, Johansson L. External validity of the
  ARISTOTLE trial in real-life atrial fibrillation
  patients.~\emph{Cardiovasc Ther} . 2014; \textbf{32} (5): 214-218.
  doi:10.1111/1755-5922.12087
\item
  Desmaele S, Steurbaut S, Cornu P, Brouns R, Dupont AG. Clinical trials
  with direct oral anticoagulants for stroke prevention in atrial
  fibrillation: how representative are they for real life
  patients?~\emph{Eur J Clin Pharmacol} . 2016; \textbf{72} (9):
  1125-1134. doi:10.1007/s00228-016-2078-1
\item
  Fanning L, Ilomaki J, Bell JS, D\selectlanguage{polish}ā\selectlanguage{english}rzi\selectlanguage{polish}ņš \selectlanguage{english}P. The representativeness of
  direct oral anticoagulant clinical trials to hospitalized patients
  with atrial fibrillation.~\emph{Eur J Clin Pharmacol} .
  2017;\textbf{73} (11): 1427-1436. doi:10.1007/s00228-017-2297-0
\item
  Hughey AB, Gu X, Haymart B, et al. Warfarin for prevention of
  thromboembolism in atrial fibrillation: comparison of patient
  characteristics and outcomes of the ''Real-World'' Michigan
  Anticoagulation Quality Improvement Initiative
  (MAQI\textsuperscript{2}) registry to the RE-LY, ROCKET-AF, and
  ARISTOTLE trials.~\emph{J Thromb Thrombolysis} . 2018; \textbf{46}
  (3): 316-324. doi:10.1007/s11239-018-1698-y
\item
  Morimoto T, Uchida K, Sakakibara F, Kinjo N, Ueda S. Effect of
  concomitant antiplatelet therapy on ischemic and hemorrhagic events in
  patients taking oral anticoagulants for nonvalvular atrial
  fibrillation in daily clinical practice.~\emph{Pharmacoepidemiol Drug
  Saf} . 2021; \textbf{30} (10): 1321-1331. doi:10.1002/pds.5228
\item
  Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ.
  Validation of clinical classification schemes for predicting stroke:
  results from the National Registry of Atrial Fibrillation.~\emph{JAMA}
  . 2001; \textbf{285} (22): 2864-2870. doi:10.1001/jama.285.22.2864
\item
  Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel
  user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding
  in patients with atrial fibrillation: the Euro Heart
  Survey.~\emph{Chest} . 2010; \textbf{138} (5): 1093-1100.
  doi:10.1378/chest.10-0134
\item
  Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of
  the Scientific and Standardization Committee of the International
  Society on Thrombosis and Haemostasis. Definition of major bleeding in
  clinical investigations of antihemostatic medicinal products in
  non-surgical patients.~\emph{J Thromb Haemost} . 2005; \textbf{3} (4):
  692-694. doi:10.1111/j.1538-7836.2005.01204.x
\item
  Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial
  Infarction (TIMI) Trial, Phase I: A comparison between intravenous
  tissue plasminogen activator and intravenous streptokinase. Clinical
  findings through hospital discharge.~\emph{Circulation} .
  1987;\textbf{76} (1):142-154. doi:10.1161/01.cir.76.1.142
\item
  Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly
  Patients with Atrial Fibrillation.~\emph{N Engl J Med} .
  2020;\textbf{383} (18): 1735-1745. doi:10.1056/NEJMoa2012883
\item
  Rothwell PM. External validity of randomised controlled trials: ''to
  whom do the results of this trial apply?''~\emph{Lancet} .
  2005;\textbf{365} (9453): 82-93. doi:10.1016/S0140-6736(04)17670-8
\end{enumerate}

\textbf{Tables}

\textbf{Table 1 Developed Inclusion /exclusion criteria for the
assessment of eligibility of our registered patients and criteria of 4
Phase III trials of DOACs}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Our study\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
RE-LY\textsuperscript{a}{[}1{]}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
ROCKET-AF\textsuperscript{b}{[}2{]}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
ARISTOTLE\textsuperscript{c}{[}4{]}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
ENGAGE TIMI48\textsuperscript{d}{[}5{]}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Inclusion\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?] 18 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?] 18 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?] 18 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?] 18 years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
[?] 21 years\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
AF\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Non-valvular atrial fibrillation\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Atrial fibrillation\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Non-valvular atrial fibrillation\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Atrial fibrillation or atrial flutter\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Paroxysmal, persistent, or permanent AF\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CHADS\textsubscript{2} Score\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CHADS\textsubscript{2} score [?] 2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
One of the following: 1. Prior stroke, TIA or SE 2. EF\textless{}40\% 3.
HF 4. Age[?]75. 5. 65[?]age\textless{}75\&(DM or HT or CAD)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CHADS\textsubscript{2} score [?] 2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CHADS\textsubscript{2} score [?] 1\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CHADS\textsubscript{2} score [?] 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Exclusion\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Bleeding Risk\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
History of major bleeding\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
History of major bleeding\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
History of major bleeding\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
History of major bleeding\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Uncontrolled hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SBP \textgreater{}180mmHg or DBP \textgreater{}100mmHg\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SBP \textgreater{} 180mmHg and/or DBP \textgreater{} 100mmHg\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SBP [?] 180mmHg or DBP [?] 100mmHg\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SBP \textgreater{}180mmHg or DBP \textgreater{} 100mmHg\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
SBP \textgreater{} 170mmHg or DBP \textgreater{} 100mmHg\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Renal function\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Calculated CLCR \textless{} 30 mL/min\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Calculated CLCR [?] 30 mL/min\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Calculated CLCR \textless{} 30 mL/min\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Serum creatinine \textgreater{} 2.5 mg/dL or a calculated CLCR
\textless{} 25\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Calculated CLCR \textless{} 30 mL/min\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hepatic function\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
ALT or AST \textgreater{} 2x the ULN, or TBL [?] 1.5x the ULN\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Active liver disease, including but not limited to a. persistent ALT,
AST, Alk Phos \textgreater{} 2x the ULN\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Known significant liver disease, or ALT \textgreater{} 3x the ULN\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
ALT or AST \textgreater{} 2x the ULN, or a Total Bilirubin [?] 1.5x the
ULN\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Active or persistent liver disease, positive hepatitis B to C test, in:
\selectlanguage{english}ALT or AST [?] 2x the ULN \selectlanguage{english}TBL [?] 1.5x the ULN\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Haemoglobin \& platelet count\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hgb \textless{} 10 g/dL or platelet count \textless{} 100,000
cells/mL\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hgb \textless{} 10 g/dL or platelet count \textless{} 100,000
cells/mL\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hgb \textless{} 10 g/dL or platelet count \textless{} 90,000
cells/mL\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hgb \textless{} 9 g/dL or platelet count [?] 100,000 cells/mL\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Hgb \textless{} 10 g/dL or platelet count \textless{} 100,000 cells/mL
or WBC \textless{} 3000cell/mL\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Antiplatelet therapy\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Aspirin in combination with thienopyridines\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Aspirin \textgreater{} 100 mg/day or Aspirin in combination with
thienopyridines\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Aspirin \textgreater{} 165 mg/day or Aspirin in combination with
thienopyridines\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Aspirin in combination with thienopyridines\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Anti-inflammatory agents\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Chronic treatment with NSAIDs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Anticipated need for chronic treatment with NSAIDs\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Chronic treatment with NSAIDs\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Concomitant Therapy\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CYP3A4 inducer CYP3A4 inhibitor\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
CYP3A4 inhibitor Macrolide antibiotics\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Cox-2 inhibitor\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Drug or alcohol dependence\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Alcohol dependence\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Drug addiction or alcohol dependence\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Drug addiction or alcohol dependence\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Drug addiction or alcohol dependence\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} The Randomised Evaluation of Long-term
Anticoagulation Therapy.

\textsuperscript{b} The Rivaroxaban Once Daily Oral Direct Factor Xa
Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke
and Embolism Trial in Atrial Fibrillation.

\textsuperscript{c} The Apixaban for the Prevention of Stroke in
Subjects With Atrial Fibrillation.

\textsuperscript{d} Effective Anticoagulation With Factor Xa Next
Generation in Atrial Fibrillation.



\textbf{Table 2 Proportion of eligible and ineligible patients according
to inclusion and exclusion criteria.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
DOACs criteria\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Eligible n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Ineligible n (\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Inclusion\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
age [?]18 years\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7826 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AF\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
non-valvular atrial fibrillation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7826 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CHADS\textsubscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CHADS\textsubscript{2} score [?] 2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5763 (73.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2063 (26.4\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Exclusion\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Haemorrhage Risk\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
History of major bleeding\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7547 (96.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
279 (3.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Uncontrolled hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
SBP \textgreater{} 180mmHg or DBP \textgreater{} 100mmHg\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7701 (98.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
125 (1.6\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Renal dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Calculated CLCR \textless{} 30 mL/min\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7085 (90.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
741 (9.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hepatic function\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ALT or AST \textgreater{} 2 times the ULN or TBL [?] 1.5 times the
ULN\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7608 (97.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
218 (2.8\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Haemoglobin \& platelet count\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hgb \textless{} 10 g/dL or platelet count \textless{} 100,000
cells/mL\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7324 (93.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
502 (6.4\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Antiplatelet therapy\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aspirin \textgreater{} 100 mg daily or Aspirin in combination with
thienopyridines\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7550 (96.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
276 (3.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Anti-inflammatory agents\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
chronic treatment with NSAIDs\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7513 (96\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
313 (4.0\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Drug or alcohol dependence\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
alcohol dependence\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7783 (99.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
43 (0.5\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Overall\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4054 (51.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3772 (48.2\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3 Baseline Characteristics of eligible and ineligible
patients with CHADS\textsubscript{2} score [?] 2.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Eligible (n=4054) & Ineligible with CHADS\textsubscript{2} [?] 2
(n=1709) & \emph{p-}value\tabularnewline
\midrule
\endhead
Age {[}yr{]} Median (Interquartile range) & 76 (69--81) & 79 (73--85) &
\textless{}.0001\tabularnewline
Female sex no. (\%) & 1320 (32.6) & 708 (41.4) &
\textless{}.0001\tabularnewline
Body Weight kg (mean) & 62.9 & 57.5 & \textless{}.0001\tabularnewline
BMI, mean (SD) & 24.7 (4.04) & 23.43 (4.31) &
\textless{}.0001\tabularnewline
Systolic Blood pressure --- mmHg Median & 128 & 126 &
0.196\tabularnewline
Paroxysmal atrial fibrillation no. (\%) & 1304 (36.9) & 467 (32.0) &
0.0011\tabularnewline
CHADS\textsubscript{2} score Mean & 2.96 & 3.24 &
\textless{}.0001\tabularnewline
CHADS\textsubscript{2} Score 2-no. (\%) & 1711 (42.2) & 508 (29.7) &
\textless{}.0001\tabularnewline
CHADS\textsubscript{2} Score [?] 3-no. (\%) & 2343 (57.8) & 1201 (70.3) &
\textless{}.0001\tabularnewline
HASBLED Score & 1.72 & 2.43 & \textless{}.0001\tabularnewline
Prior stroke or transient ischemic attack no. (\%) & 1270 (31.4) & 599
(35.2) & 0.0047\tabularnewline
Age [?] 75yr -- no. (\%) & 2324 (57.3) & 1198 (70.1) &
\textless{}.0001\tabularnewline
Heart failure -- no. (\%) & 2020 (50.1) & 1074 (63.6) &
\textless{}.0001\tabularnewline
Diabetes mellitus-- no. (\%) & 1642 (40.5) & 707 (41.4) &
0.546\tabularnewline
Hypertension-- no. (\%) & 3552 (87.7) & 1497 (87.7) &
0.989\tabularnewline
CAD--no. (\%) & 1111 (27.5) & 653 (38.4) &
\textless{}.0001\tabularnewline
\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}ACS--no. (\%) & 422 (10.6) & 308 (18.5) &
\textless{}.0001\tabularnewline
PCI & 286 (7.2) & 318 (19.1) & \textless{}.0001\tabularnewline
CABG & 125 (3.1) & 101 (6.0) & \textless{}.0001\tabularnewline
COPD & 177 (4.4) & 93 (5.5) & 0.076\tabularnewline
Chronic liver disease--no. (\%) & 290 (7.2) & 183 (10.7) &
\textless{}.0001\tabularnewline
History of cancer--no. (\%) & 453 (11.2) & 254 (14.9) &
\textless{}.0001\tabularnewline
History of RFCA--no. (\%) & 261 (6.5) & 70 (4.1) & 0.0004\tabularnewline
CCr mean (SD) & 63.68 (24.7) & 44.59 (27.5) &
\textless{}.0001\tabularnewline
PT-INR mean (SD) & 1.91 (0.38) & 1.87 (0.41) & 0.0006\tabularnewline
TTR mean (SD) & 74.69 (33.34) & 68.91 (35.51) &
\textless{}.0001\tabularnewline
ASA--no. (\%) & 805 (19.9) & 612 (35.9) &
\textless{}.0001\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4 Outcomes of eligible and ineligible patients with
CHADS\textsubscript{2} score [?] 2.}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Outcome & Eligible (n=4054) & Eligible (n=4054) & Ineligible \&
CHADS\textsubscript{2} [?] 2 (n=1709) & Ineligible \&
CHADS\textsubscript{2} [?] 2 (n=1709) & Hazard ratio (95\% CI) &
\emph{P}-value\tabularnewline
\midrule
\endhead
& No. of events & Event rate, \%/yr & No. of events & Event rate, \%/yr
& &\tabularnewline
Major bleeding & 224 & 1.83 & 163 & 3.67 & 2.00 (1.63--2.44) &
\textless{}0.0001\tabularnewline
Stroke/SE & 156 & 1.27 & 87 & 1.93 & 1.53 (1.17--1.98) &
0.0016\tabularnewline
Death from any cause & 213 & 1.70 & 221 & 4.82 & 2.84 (2.36--3.43) &
\textless{}0.0001\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 5 Baseline characteristics of eligible and ineligible
patients, including patients with CHADS\textsubscript{2}\textless{}2.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& All & Eligible (n=4054) & Ineligible (n=3772) &
\emph{P-}value\tabularnewline
\midrule
\endhead
Age yr Median (Interquartile range) & 74 (66--80) & 76 (69--81) & 71
(64--80) & \textless{}.0001\tabularnewline
Female sex no. (\%) & 2552 (33) & 1320 (32.6) & 1232 (32.7) &
0.923\tabularnewline
Body Weight kg, mean & 62.3 & 62.9 & 61.6 &
\textless{}.0001\tabularnewline
BMI, mean (SD) & 24.4 (4.11) & 24.7 (4.04) & 24.0 (4.16) &
\textless{}.0001\tabularnewline
Systolic Blood pressure -- mmHg Mean & 126 & 127 & 126 &
0.0004\tabularnewline
Paroxysmal atrial fibrillation no. (\%) & 2643 (38.7) & 1304 (36.9) &
1339 (40.6) & 0.0016\tabularnewline
CHADS\textsubscript{2} score Mean & 2.44 & 2.96 & 1.89 &
\textless{}.0001\tabularnewline
CHADS\textsubscript{2} Score 0-1-no. (\%) & 2063 (26.3) & 0 (0) & 1569
(41.6) & \textless{}.0001\tabularnewline
CHADS\textsubscript{2} Score 2-no. (\%) & 2252 (28.8) & 1711 (42.2) &
541 (14.3) & \textless{}.0001\tabularnewline
CHADS\textsubscript{2} Score [?] 3-no. (\%) & 3511 (44.9) & 2343 (57.8) &
1201 (31.8) & \textless{}.0001\tabularnewline
HASBLED Score & 1.73 & 1.73 & 1.73 & 0.976\tabularnewline
Prior stroke or transient ischemic attack no. (\%) & 1903 (24.3) & 1270
(31.4) & 633 (16.8) & \textless{}.0001\tabularnewline
Age [?] 75yr -- no. (\%) & 3755 (48.0) & 2324 (57.3) & 1431 (37.9) &
\textless{}.0001\tabularnewline
Heart failure -- no. (\%) & 3291 (42.4) & 2020 (50.1) & 1271 (34.1) &
\textless{}.0001\tabularnewline
Diabetes mellitus-- no. (\%) & 2444 (31.2) & 1642 (40.5) & 802 (21.3) &
\textless{}.0001\tabularnewline
Hypertension-- no. (\%) & 6119 (78.2) & 3552 (87.7) & 2567 (68.1) &
\textless{}.0001\tabularnewline
CAD--no. (\%) & 2075 (27) & 1111 (27.5) & 964 (25.7) &
0.066\tabularnewline
ACS--no. (\%) & 819 (10.6) & 422 (10.6) & 397 (10.7) &
0.813\tabularnewline
PCI--no. (\%) & 684 (8.9) & 286 (7.2) & 398 (10.7) &
\textless{}.0001\tabularnewline
CABG--no. (\%) & 246 (3.2) & 125 (3.1) & 121 (3.2) &
0.767\tabularnewline
COPD--no. (\%) & 330 (4.2) & 177 (4.4) & 153 (4.1) &
0.496\tabularnewline
Chronic liver disease--no. (\%) & 606 (7.8) & 290 (7.2) & 316 (8.4) &
0.0425\tabularnewline
History of cancer--no. (\%) & 875 (11.2) & 453 (11.2) & 422 (11.2) &
0.972\tabularnewline
History of RFCA--no. (\%) & 623 (8.0) & 261 (6.5) & 362 (9.7) &
\textless{}.0001\tabularnewline
CCr mean (SD) & 63.03 (28.75) & 63.68 (24.7) & 62.34 (32.37) &
0.0486\tabularnewline
PT-INR mean (SD) & 1.90 (0.38) & 1.91 (0.38) & 1.89 (0.39) &
0.0110\tabularnewline
TTR mean (SD) & 73.35 (33.8) & 74.69 (33.34) & 71.91 (34.22) &
0.0003\tabularnewline
ASA--no. (\%) & 168 4(22) & 805 (19.93) & 879 (23.36) &
0.0002\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure legends}

Figure 1. Flow diagram of registered patients

Figure 2. Cumulative incidence of major bleeding (panel a),
stroke/systemic embolism (panel b), and all-cause death (panel c) in
eligible and ineligible patients with CHADS\textsubscript{2} score [?] 2.

\textbf{Hosted file}

\verb`Figures(1,2) Higa.pptx`  available at \url{https://authorea.com/users/655334/articles/661186-outcomes-of-real-world-patients-with-non-valvular-atrial-fibrillation-on-anticoagulants-ineligible-for-phase-iii-trials-of-direct-oral-anticoagulants}

\selectlanguage{english}
\FloatBarrier
\end{document}

