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\begin{document}

\title{Appropriate Use of Aspirin in the Primary and Secondary Prevention:
Results From the ASSOS Study}



\author[1]{OĞUZHAN ÇELİK}%
\author[1]{CEM ÇİL}%
\author[1]{ÖZCAN BAŞARAN}%
\author[2]{ERKAN DEMIRCI}%
\author[3]{VEYSEL TANIK}%
\author[4]{EMINE ALTUNTAS}%
\author[5]{KADRIYE MEMIC SANCAR}%
\author[6]{Ozcan Orscelik}%
\author[7]{MUCAHIT YETIM}%
\author[7]{LUTFU BEKAR}%
\author[7]{OSMAN KARAARSLAN}%
\author[1]{BULENT OZLEK}%
\author[1]{EDA ÖZLEK}%
\author[1]{AYSEL GOKCEK}%
\author[8]{TOLGA DOGAN}%
\author[9]{MUBARIZ MURAT RESULZADE}%
\author[10]{CAGLAR KAYA}%
\author[11]{EMRAH KUCUK}%
\author[12]{TUNCAY KIRIS}%
\author[13]{Abdullah Orhan Demirtas}%
\author[14]{MURAT CIVAN}%
\author[15]{RAMAZAN ASOGLU}%
\author[1]{VOLKAN DOĞAN}%
\author[1]{MURAT BİTEKER}%
\affil[1]{Mugla Sitki Kocman University Faculty of Medicine}%
\affil[2]{Ministry of Health Kayseri City Hospital}%
\affil[3]{Ankara Diskapi Yildirim Beyzat Training and Research Hospital}%
\affil[4]{Sancaktepe Şehit Prof Dr Ilhan Varank Training and Research Hospital}%
\affil[5]{Mehmet Akif Ersoy Thoracic and Cardiovascular Research and Education Hospital}%
\affil[6]{Mersin University Hospital}%
\affil[7]{Hitit University Faculty of Medicine}%
\affil[8]{Bursa Yuksek Ihtisas Training and Research Hospital}%
\affil[9]{Kartal Kosuyolu Training and Research Hospital}%
\affil[10]{Trakya University Hospital}%
\affil[11]{Zonguldak Bulent Ecevit Universitesi Tip Fakultesi}%
\affil[12]{Izmir Katip Celebi University Faculty of Medicine}%
\affil[13]{Saglik Bilimleri Universitesi}%
\affil[14]{Nisantasi Universitesi}%
\affil[15]{Adiyaman Universitesi Egitim ve Arastirma Hastanesi}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: Indications and appropriateness of aspirin use have not been
well investigated in Turkey. Therefore, the aim of this study is to
investigate the prescription patterns and appropriateness of aspirin in
a real-world clinical setting. Methods: The ASSOS study is a
cross-sectional, multicenter registry involving consecutive cardiology
patients who were using aspirin. Patients were divided into two groups
according to the use of aspirin; primary prevention and secondary
prevention group. The indication of aspirin use was evaluated according
to 2016 the European Society of Cardiology (ESC) and 2016 the United
States Preventative Services Task Force (USPTF) guidelines in the
primary prevention group. Results: A total of 5007 patients (mean age
62.15\selectlanguage{ngerman}± 11.05, 39\% female) were enrolled. The primary prevention group
included 1132 (22.6\%) patients and the secondary prevention group
included 3875 (77.4\%) patients. Of the 1132 patients, inappropriate use
of aspirin was determined in 100\% of the patients according to the ESC
guidelines, and 71 \% of the patients according to the USPTF guidelines.
Conclusion: Although there are considerable differences between the
USPTF and the ESC guidelines with respect to recommendations for aspirin
use in primary prevention, inappropriate use of aspirin in Turkey is
frequent in real-world practice for both guidelines.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Cardiovascular diseases (CVD) are responsible for nearly half of all
deaths globally (1). Minimizing the impact of CVD and related
disabilities is a major challenge and aspirin is the oldest and most
reliable drug for this purpose (2). It is an indispensable drug in the
secondary prevention of CVD (2). The net benefit is well established and
supported by a large body of evidence for secondary prevention patients
(3-5). However, there is no clear consensus on whom aspirin therapy is
appropriate for the primary prevention of CVD.

The 2016 European Society of Cardiology (ESC) guidelines on CVD
prevention did not recommend aspirin therapy in primary prevention due
to increased risk of bleeding (6). While this recommendation includes
both patients with and without diabetes mellitus (DM) in European
guidelines, the American Diabetes Association (ADA) 2018 guidelines
recommend aspirin therapy in patients with DM aged 50 years or older
with at least one additional CVD risk factor, without increased risk of
bleeding (7). In parallel, 2016 United States Preventative Services Task
Force (USPTF) (8) and 2019 American College of Cardiology/ American
Heart Association (ACC/AHA) guidelines on the primary prevention of CVD
states that aspirin (75-100 mg/day) might be used in selected patients
aged 40 to 70 who have high CVD risk but not increased bleeding risk
(9).

Recently, three large-scale randomized controlled trials evaluated the
use of aspirin in the primary prevention of CVD. These trials provided
further evidence for the use of aspirin in primary prevention. The
Aspirin in Reducing Events in the Elderly (ASPREE) trial enrolled
elderly patients (10), the Aspirin to Reduce Risk of Initial Vascular
Events (ARRIVE) trial enrolled patients with moderate to high CVD risk
(11), and the A Study of Cardiovascular Events iN Diabetes (ASCEND)
trial enrolled patients with DM (12). While ARRIVE and ASPREE trials
showed no benefit in terms of CVD risk reduction, only the ASCEND trial
indicated a lower rate of major CV events, but this effect was
attenuated by a higher rate of major bleeding. There was no all-cause
mortality benefit in these trials (9-11). However, indications,
prescription patterns, and appropriateness of aspirin use have not been
well investigated with randomized or observational studies in Turkey.
Therefore, the Appropriateness of Aspirin Use in Medical Outpatients: A
Multicenter, Observational Study (ASSOS) aims to investigate the
potential misuse of aspirin in both primary and secondary prevention
patients. The ASSOS is the largest multicenter domestic trial regarding
this topic. The use of aspirin therapy was evaluated taking into account
the risk of CVD and bleeding in this real-world trial.

\textbf{Methods}

\textbf{Study design}

The design of the ASSOS trial has already been described in detail (13).
In brief, the ASSOS study was an observational and cross-sectional
national registry study. The study was performed by 30 cardiologists in
14 different cities and the data was collected during a routine
ambulatory visit from March 1, 2018, to June 31, 2018. All consecutive
patients admitted to the outpatient cardiology clinics who have been
prescribed aspirin, irrespective of the indication for use, were
included. The study did not stipulate any diagnostic or treatment
procedures. The study was approved by the Institutional Review Board of
Local Ethics Committee (Mu\selectlanguage{polish}ğ\selectlanguage{english}la S\selectlanguage{polish}ı\selectlanguage{english}tk\selectlanguage{polish}ı \selectlanguage{english}Kocman University Faculty of
Medicine) and registered at ClinicalTrials.gov (NCT03387384).

The number of patients was proportional to the population of each 7
regions of Turkey. Patients aged 18 years or older at the time of
enrollment, willing to participate and provided written consent, and
treated with aspirin (75--100 mg) within the last 30 days were included.
Pregnant patients, minors \textless{}18 years, and patients with a
mental disorder were excluded.

Patients were divided into two groups according to the use of aspirin;
primary prevention group patients were defined as participants who did
not have any clinically apparent CVD and secondary prevention group
patients were the participants who had documented CVD manifested by
fatal or non-fatal myocardial infarction, angina pectoris, aortic
atherosclerosis and thoracic or abdominal aortic aneurysm, peripheral
artery disease manifested by intermittent claudication and critical limb
ischemia, and cerebrovascular disease manifested by fatal or non-fatal
stroke and transient ischemic attack.

\textbf{Data}

Demographic and clinical characteristics of the participants included
age, gender, educational status, smoking history, place of residence
(rural or urban), body mass index, and alcohol use.

Medical history, cardiovascular risk factors, and all comorbidities,
physical examination details, and all concomitant medications were
questioned. The duration for aspirin therapy, the reason of use (primary
or secondary prevention), and the specialty of the physician who
prescribed aspirin were analyzed.

The indication of aspirin use was assessed according to the 2016 ESC (6)
and 2016 United States Preventative Services Task Force (USPTF)
guidelines (8). The risk of experiencing an atherosclerotic event was
calculated using an online atherosclerotic cardiovascular disease
(ASCVD) risk calculator prepared according to the 2013 ACC/AHA
guidelines (14) for each individual in the primary prevention group.

The bleeding risk was determined by HASBLED and other clinical
parameters. The HASBLED score adds one point for hypertension, abnormal
renal/liver function (one point each), stroke, bleeding history or
predisposition, labile international normalized ratio, age 65 and older,
and drugs/alcohol concomitantly (one point each) (15). Risk factors for
gastrointestinal bleeding with aspirin use, such as higher dose and
longer duration of use, history of gastrointestinal bleeding, bleeding
disorders, ulcers or upper gastrointestinal pain, thrombocytopenia,
renal failure, severe liver disease, concurrent anticoagulation or
nonsteroidal anti-inflammatory drug use, and uncontrolled hypertension
were analyzed.

Risk factors for colorectal cancer, such as a history of colonic
adenomatous polyps, family or personal history of colorectal cancer or
familial adenomatous polyposis, alcohol intake, obesity, and smoking
were also noted.

\textbf{Definiton of Appropriate Use of Aspirin}

The appropriate use of aspirin was evaluated according to the USPTF and
ESC guidelines in the primary prevention group. The ESC guidelines do
not recommend aspirin for primary prevention (6). The USPTF guidelines
suggest aspirin for adults age 40 to 70 at higher risk of
atherosclerotic CVD without higher bleeding risk (8). Therefore, we
defined aspirin use as inappropriate for all patients according to the
ESC guidelines and for patients younger than 40, elder than 70, ASCVD
score \textless{} 10\% and, in those at high bleeding risk according to
the USPTF guidelines.

\textbf{Statistical analysis}

Mean \selectlanguage{ngerman}± standard deviation or median and interquartile range was used for
continuous variables. Categorical variables were summarized as
frequencies and percentages. Continuous variables were compared using
univariate analysis, and the chi-square test or Fisher exact test were
performed for categorical variables. Multivariate logistic regression
analysis was performed to find independent predictors of inappropriate
aspirin use. A p-value \textless{}0.05 was considered statistically
significant. Statistical analysis was performed using statistical
software (SPSS version 13.0, SPSS, Chicago, IL, USA).

\textbf{Results}

A total of 5007 patients (1955 females, 39\%) were enrolled and divided
into primary prevention~and~secondary prevention groups according to the
use of aspirin. The primary prevention group included 1132 (22.6\%)
patients and the secondary prevention group included 3875 (77.4\%)
patients.

\textbf{Comparison of Primary and Secondary Prevention Groups}

Baseline demographic characteristics, comorbid diseases of the
population demonstrated in \textbf{Table 1} . There were no significant
differences between the two groups in terms of age, place of residence,
the prevalence of a chronic pulmonary disease, or hepatic failure.
However, patients in the secondary prevention group were more likely to
be male, had a higher prevalence of DM, heart failure, hyperlipidemia,
tobacco, and alcohol use. Primary prevention group patients had a higher
prevalence of hypertension and atrial fibrillation compared to patients
in the secondary prevention group. HASBLED scores were higher in the
secondary prevention group (\textbf{Table 1)} . While 45.9\% of the
patients with a HASBLED score\textgreater{} 2 were on proton pump
inhibitor (PPI), 40.8\% of HASBLED\selectlanguage{english}[?] 2 were on PPI (p= 0. 010).

Aspirin treatment was initiated most frequently by cardiologists
(n=4167, 83.2\%), followed by specialists of internal medicine (n=265,
5.3\%) and neurology (n=259, 5.2\%). Aspirin was used more often in
secondary prevention than primary prevention by cardiologists and
cardiovascular surgeons (\textbf{Fig 1} ). Other specialists prescribed
aspirin mainly for primary prevention.

\textbf{Appropriate Use of Aspirin in the Primary Prevention Group}

Aspirin use was inappropriate in all primary prevention patients
according to ESC guidelines. Of the primary prevention patients whose
ages were between 40-70 years, 324 were at high (\selectlanguage{english}[?]10\%) ASCVD risk and
low bleeding risk (HASBLED\selectlanguage{english}[?] 2) whereas 52 were at high (\selectlanguage{english}[?]10\%) ASCVD
risk and high bleeding (HASBLED\textgreater{}2) risk (\textbf{Fig 2} ).
Therefore, 808 of the 1132 patients (71 \%) accepted as inappropriate
use of aspirin according to the USPTF guidelines. Univariate analysis
showed being female, older age, smoking, educational status
(illiterate), having hypertension, atrial fibrillation, heart failure,
hyperlipidemia, diabetes mellitus, major bleeding history and being on
OAC therapy were associated with inappropriate use of aspirin
(\textbf{Table 2} ). Multivariate analysis was performed to find
independent predictors of inappropriate use of aspirin in primary
prevention patients. Female sex, oral anticoagulant use and heart
failure were independent predictors of inappropriate aspirin use.
However older age, smoking, hypertension, diabetes mellitus were
associated with appropriate of aspirin use (\textbf{Table 3} ).

\textbf{Discussion}

Our study showed that in a large real-world cohort of aspirin users,
nearly one-fourth of the patients were receiving the drug for primary
prevention. The other main findings of our study were: 1- female
patients were more likely to be prescribed aspirin for primary
prevention compared to males; 2- aspirin was prescribed more often for
primary prevention than secondary prevention by specialists other than
the cardiologists and cardiovascular surgeons; 3- the rate of
inappropriate use of aspirin was high according to both ESC and USPTF
guidelines in the real-world practice; 4- independent predictors of
inappropriate aspirin use were female sex, oral anticoagulant use and
heart failure in primary prevention patients and older age, smoking,
hypertension, diabetes mellitus were associated with appropriate use of
aspirin.

Although aspirin has been used in the secondary prevention of
atherosclerotic events for more than 40 years (16), it has acquired a
negative image in primary prevention trials which showed that aspirin
did not reduce the overall mortality and did not have a net benefit
(10-12).

However, there are different recommendations between the European and
American guidelines regarding the use of aspirin in primary prevention.
The ESC guidelines recommended that aspirin should not be used for
primary prevention and subjects without clinical manifestations of CVD
should not take aspirin (class III, level A) (6).

The USPTF guidelines recommended that low-dose aspirin might be
considered in persons of 40 to 70 years of age who were at higher CVD
risk but not at increased bleeding risk (class IIb, level A), whereas it
should not be routinely administered in subjects aged \textgreater{}70
years (class III, level B) and should be avoided in subjects of any age
at increased risk of bleeding (class III, level C) (8). The presence of
such differences between the guidelines usually leads to physicians
having different treatment recommendations for patients without overt
CVD. However, indications and the appropriateness of aspirin use were
not well studied among Turkish patients. In the awareness, efficacy,
safety, and time in the therapeutic range of warfarin in the Turkish
population study (WARFARIN-TR) all consecutive patients using warfarin
were enrolled to evaluate the prevalence of the inappropriate
combination of aspirin and warfarin therapy (17). Although performed on
a very different patient population, the WARFARIN-TR study revealed that
one-fifth of patients who receive warfarin were receiving aspirin
inappropriately (17).

Data is very limited about patterns of inappropriate aspirin use in
Turkey but studies from Europe (18) and the US (19,20) have previously
documented overutilization of aspirin for primary prevention. Manes and
colleagues screened 20,599 patients in Italy and determined 400 patients
were on treatment with aspirin for primary prevention (18). The authors
found an overprescription of aspirin in 18\% of the 400 patients. In a
cross-sectional study, individuals aged 30--79 years in the Marshfield
Epidemiologic Study Area were analyzed in the US (19). This study showed
that 19\% of the 16,922 individuals who were not clinically indicated
for aspirin therapy for primary CVD were regular aspirin users (19). In
the last study, 68,808 patients receiving aspirin for primary prevention
were assessed in the US and inappropriate aspirin use frequency was
detected in 11.6\% of the study cohort (20). However, all of these
studies performed before the publication of large randomized clinical
trials (10-12) examining the use of aspirin in primary prevention, and
all of these studies used different definitions for inappropriate
aspirin use such as a 10- year risk of a CVD event \textless{}6\% or a
cardiovascular risk \textless{}1.0 event/100 patients/year. In our
study, we used the definitions of current guidelines and found that
inappropriate aspirin use frequency was 100\% according to ESC and 71\%
according to USPTF guidelines. The current study also showed that 56\%
of the primary prevention group were female. (The current study is
comprised of 56\% female in the primary prevention group.) We also
detected that aspirin was usually preferred and initiated by specialists
other than cardiologists and cardiovascular surgeons in the primary
prevention group.

Prevalence of aspirin use in primary prevention of cardiovascular
disease was found 23.4\% among adults 40 years or older in the National
Health Interview Survey from the US. Of those 22.8\% were using aspirin
without a physician's recommendation. Of note older age, male sex, and
cardiovascular risk factors (hypertension, hyperlipidemia, diabetes, and
smoking) were statistically significantly associated with aspirin use in
this study (21). Similarly, our study showed female sex, oral
anticoagulant use and heart failure were independent predictors of
inappropriate aspirin use, and older age, smoking, hypertension,
diabetes mellitus were associated with appropriate use of aspirin.

The results of the ASSOS study revealed the overuse of aspirin in
low-risk patients despite the recent introduction of randomized
controlled trials and international guidelines, suggesting the need for
improved management of patients who had no overt CVD.

\textbf{Limitations:}

The present study has a cross-sectional design and the safety and
efficacy outcomes could not be assessed. ASSOS study was conducted in
different outpatient cardiology clinics however, participating
institutions were geographically distributed across the country.

\textbf{Conclusions}

To the best of our knowledge, the ASSOS study cohort represents the
largest number of patients treated with aspirin in Turkey. The present
study provides contemporary data on aspirin use both in primary
prevention and secondary prevention group patients. The results of our
study suggest that the overuse of aspirin is common because of
physicians' poor compliance with the guideline recommendations in
patients without documented CVD. Female patients who were on oral
anticoagulants and had heart failure were at the highest risk for
inappropriate use of aspirin however, older age, smoking, hypertension,
diabetes mellitus were associated with appropriate use of aspirin. Thus,
a greater emphasis should be given to these patients' characteristics.

\textbf{Figure Legend}

\textbf{Figure 1.} Distribution of aspirin use in secondary and primary
prevention according to specialists

\textbf{Figure 2.} Distribution of primary prevention patients between
the ages of 40-70 according to ASCVD and HASBLED score

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Leong DP, Joseph PG, McKee M, Anand SS, Teo KK, Schwalm JD, Yusuf S.
  Reducing the Global Burden of~Cardiovascular~Disease, Part 2:
  Prevention and Treatment of~Cardiovascular~Disease. Circ Res. 2017 Sep
  1;121(6):695-710.
\item
  Montinari MR, Minelli S, De Caterina R. The first 3500 years
  of~aspirin~history from its roots - A concise summary. Vascul
  Pharmacol. 2019 Feb;113:1-8.
\item
  Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of
  aspirin against acute myocardial infarction and death in men with
  unstable angina. Results of a Veterans Administration Cooperative
  Study. N Engl J Med 1983;309(07):396--403.
\item
  Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both
  in unstable angina. Results of a Canadian multicenter trial. N Engl J
  Med 1985;313(22):1369--1375.
\item
  ISIS-2 (Second International Study of Infarct Survival) Collaborative
  Group. Randomised trial of intravenous streptokinase, oral aspirin,
  both, or neither among 17,187 cases of suspected acute myocardial
  infarction: ISIS-2. Lancet 1988;2(8607):349--360.
\item
  Piepoli MF, Hoes AW, Agewall S, et al; ESC Scientific Document Group.
  2016 European Guidelines on cardiovascular disease prevention in
  clinical practice: the Sixth Joint Task Force of the European Society
  of Cardiology and Other Societies on Cardiovascular Disease Prevention
  in Clinical Practice (constituted by representatives of 10 societies
  and by invited experts): developed with the special contribution of
  the European Association for Cardiovascular Prevention \&
  Rehabilitation (EACPR). Eur Heart J 2016;37(29):2315--2381.
\item
  Cardiovascular disease and risk management: standards of medical care
  in diabetes---2019. Diabetes Care.~2019~January. 2018:S86-S104
\item
  Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin use
  for the primary prevention of cardiovascular disease and colorectal
  cancer: U.S. Preventive Services Task Force recommendation statement.
  Ann Intern Med 2016; 164: 836-45.
\item
  Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on
  the primary prevention of cardiovascular disease: executive summary: a
  report of the American College of Cardiology/American Heart
  Association Task Force on Clinical Practice Guidelines. J Am Coll
  Cardiol 2019;74(10):1376--1414.
\item
  McNeil JJ, Nelson MR, Woods RL, et al; ASPREE Investigator Group.
  Effect of aspirin on all-cause mortality in the healthy elderly. N
  Engl J Med 2018;379(16):1519--1528.
\item
  Gaziano JM, Brotons C, Coppolecchia R, et al; ARRIVE Executive
  Committee. Use of aspirin to reduce risk of initial vascular events in
  patients at moderate risk of cardiovascular disease (ARRIVE): a
  randomised, double-blind, placebo-controlled trial. Lancet 2018;
  392(10152):1036--1046.
\item
  Bowman L, Mafham M, Wallendszus K, et al; ASCEND Study Collaborative
  Group. Effects of aspirin for primary prevention in persons with
  diabetes mellitus. N Engl J Med 2018;379(16): 1529--1539.
\item
  \selectlanguage{polish}\emph{Oğuzhan Çelik}\selectlanguage{ngerman}\textsuperscript{~},~\emph{Cem Çil} ,~\emph{Bülent
  Özlek} ,~et al. Design and rationale for the ASSOS study:
  Appropriateness of aspirin use in medical outpatients a multicenter
  and observational study. Anatol J Cardiol.~2018 Dec;20(6):354-362.
\item
  Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, et al. 2013 ACC/AHA
  guideline on the assessment of cardiovascular risk: a report of the
  American College of Cardiology/American Heart Association Task Force
  on Practice Guidelines. Circulation. 2014;129(suppl 2):S49-S73.
\item
  Shah RR, Pillai A, Omar A, Zhao J et al. Utility of the HAS-BLED Score
  in Risk Stratifying Patients on Dual Antiplatelet Therapy Post 12
  Months After Drug-Eluting Stent Placement. Catheter Cardiovasc Interv
  2017; 89: E99-E103.
\item
  Alan P Jacobsen, Inbar Raber, Cian P McCarthy et al. Lifelong Aspirin
  for All in the Secondary Prevention of Chronic Coronary Syndrome:
  Still Sacrosanct or Is Reappraisal Warranted? Circulation. 2020 Oct
  20;142(16):1579-1590. doi: 10.1161/CIRCULATIONAHA.120.045695.
\item
  Salih K\selectlanguage{polish}ı\selectlanguage{english}l\selectlanguage{polish}ı\selectlanguage{ngerman}ç, Ahmet Çelik, Elif Çekirdekçi, et al. The Prevalence and
  Risks of Inappropriate Combination of Aspirin and Warfarin in Clinical
  Practice: Results From WARFARIN-TR Study. Balkan Med J. 2019
  1;36(1):17-22.
\item
  Manes C, Giacci L, Sciartilli A, D'Alleva A, De Caterina R. Aspirin
  overprescription in primary cardiovascular prevention. Thromb Res.
  2006;118:471--477.
\item
  Jeffrey J VanWormer, Aaron W Miller, Shereif H Rezkalla. Aspirin
  overutilization for the primary prevention of cardiovascular disease.
  Clin Epidemiol . 2014 Dec 1;6:433-40.
\item
  Ravi S Hira\textsuperscript{~},~Kevin
  Kennedy\textsuperscript{~},~Vijay Nambi\textsuperscript{~},~et
  al\textsuperscript{~}. Frequency and practice-level variation in
  inappropriate aspirin use for the primary prevention of cardiovascular
  disease: insights from the National Cardiovascular Disease Registry's
  Practice Innovation and Clinical Excellence registry. J Am Coll
  Cardiol.~2015 Jan 20;65(2):111-21.
\item
  Colin W O'Brien, Stephen P Juraschek,\textsuperscript{~}~Christina C
  Wee. Prevalence of Aspirin Use for Primary Prevention of
  Cardiovascular Disease in the United States: Results From the 2017
  National Health Interview Survey. Ann Intern Med.~2019 Oct
  15;171(8):596-598. doi: 10.7326/M19-0953.~Epub 2019 Jul 23.
\end{enumerate}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

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