Original Investigation | Cardiology

Assessment of Sex Disparities in Nonacceptance of Statin Therapy

and Low-Density Lipoprotein Cholesterol Levels Among Patients
at High Cardiovascular Risk
C. Justin Brown, PharmD; Lee-Shing Chang, MD; Naoshi Hosomura, DDS, DMSc, MBA; Shervin Malmasi, PhD; Fritha Morrison, PhD; Maria Shubina, ScD;
Zhou Lan, PhD; Alexander Turchin, MD, MS

Abstract Key Points

Question How are sex disparities in
IMPORTANCE Many patients at high cardiovascular risk—women more commonly than men—are
nonacceptance of statin therapy
not receiving statins. Anecdotally, it is common for patients to not accept statin therapy
associated with control of low-density
recommendations by their clinicians. However, population-based data on nonacceptance of statin
lipoprotein (LDL) cholesterol levels?
therapy by patients are lacking.
Findings In this cohort study of 24 212
OBJECTIVES To evaluate sex disparities in nonacceptance of statin therapy and assess their adults at high cardiovascular risk,
association with low-density lipoprotein (LDL) cholesterol control. patients who accepted a statin therapy
recommendation by their clinicians
DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted from January achieved an LDL cholesterol level of less
1, 2019, to December 31, 2022, of statin-naive patients with atherosclerotic cardiovascular disease, than 100 mg/dL in a median time of 1.5
diabetes, or LDL cholesterol levels of 190 mg/dL (to convert to millimoles per liter, multiply by years vs 4.4 years for patients who did
0.0259) or more who were treated at Mass General Brigham between January 1, 2000, and not accept statin therapy. Women were
December 31, 2018. significantly less likely than men to
accept statin therapy recommendations
EXPOSURE Recommendation of statin therapy by the patient’s clinician, ascertained from the and achieve an LDL cholesterol level of
combination of electronic health record prescription data and natural language processing of less than 100 mg/dL.
electronic clinician notes.
Meaning This study suggests that
patients who do not accept statin
MAIN OUTCOMES AND MEASURES Time to achieve an LDL cholesterol level of less than
therapy have significantly higher LDL
100 mg/dL.
cholesterol levels; sex disparities in
statin acceptance could be associated
RESULTS Of 24 212 study patients (mean [SD] age, 58.8 [13.0] years; 12 294 women [50.8%]), 5308
with cardiovascular risk for women.
(21.9%) did not accept the initial recommendation of statin therapy. Nonacceptance of statin therapy
was more common among women than men (24.1% [2957 of 12 294] vs 19.7% [2351 of 11 918];
P < .001) and was similarly higher in every subgroup in the analysis stratified by comorbidities. In + Supplemental content
multivariable analysis, female sex was associated with lower odds of statin therapy acceptance (0.82 Author affiliations and article information are
[95% CI, 0.78-0.88]). Patients who did vs did not accept a statin therapy recommendation achieved listed at the end of this article.

an LDL cholesterol level of less than 100 mg/dL over a median of 1.5 years (IQR, 0.4-5.5 years) vs 4.4
years (IQR, 1.3-11.1 years) (P < .001). In a multivariable analysis adjusted for demographic
characteristics and comorbidities, nonacceptance of statin therapy was associated with a longer time
to achieve an LDL cholesterol level of less than 100 mg/dL (hazard ratio, 0.57 [95% CI, 0.55-0.60]).

CONCLUSIONS AND RELEVANCE This cohort study suggests that nonacceptance of a statin
therapy recommendation was common among patients at high cardiovascular risk and was
particularly common among women. It was associated with significantly higher LDL cholesterol
levels, potentially increasing the risk for cardiovascular events. Further research is needed to

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

understand the reasons for nonacceptance of statin therapy by patients and to develop methods to
ensure that all patients receive optimal therapy in accordance with their preferences and priorities.

JAMA Network Open. 2023;6(2):e231047. doi:10.1001/jamanetworkopen.2023.1047

Introduction
The benefits of statin therapy for patients at high cardiovascular risk are well established.1-3 However,
many of these individuals are not being treated with statins.4-6 This lack of statin therapy is
particularly pronounced among women.7-11
The reasons for the lack of statin therapy among patients at high cardiovascular risk and for the
persistent sex disparity are not fully understood and are likely multifactorial.12-15 One possible reason
for the lack of recommended therapy that has recently come to light is nonacceptance of clinicians’
treatment recommendations by patients.16,17 Anecdotal evidence and patient surveys suggest that
this phenomenon is also associated with the lack of indicated statin therapy,15 but there is a dearth of
population-based studies on the subject. The extent to which nonacceptance of statins by patients
is associated with the sex disparities in statin therapy is unknown.
A major reason for the paucity of research in this area is that information on nonacceptance of
statin therapy recommendations by patients is not easily available. This information is typically not
reflected in administrative data or structured data in the electronic health record (EHR). Instead,
nonacceptance of statin therapy by patients is recorded primarily in narrative notes, requiring labor-
intensive medical record reviews to study them. Over the last decade, however, technology for
computational analysis of narrative electronic documents—natural language processing (NLP)—has
become available, providing a powerful tool to investigate patient care processes that are
documented only in narrative documents.18-20 This technology was used in the present study to test
the hypothesis that nonacceptance by patients of a statin therapy recommendation is significantly
associated with a lack of statin treatment among patients at high cardiovascular risk and specifically
associated with sex disparities in statin therapy.

Methods
This study was approved by the Mass General Brigham institutional review board, and the
requirement for informed consent was waived because of the low risk of adverse effects to study
participants. We followed the Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE) reporting guideline.

Study Design
This retrospective cohort study was conducted from January 1, 2019, to December 31, 2022, among
patients at high cardiovascular risk with elevated low-density lipoprotein (LDL) cholesterol levels.
The study investigated the association between a patient’s decision to accept a statin therapy
recommendation and the time to achieve an LDL cholesterol level of less than 100 mg/dL (to convert
to millimoles per liter, multiply by 0.0259) as well as patient characteristics associated with
acceptance of statin therapy.

Study Cohort
Study patients included adults at high cardiovascular risk treated in practices affiliated with Mass
General Brigham (a large integrated health care delivery network in Massachusetts founded by
Brigham and Women’s Hospital and Massachusetts General Hospital) between January 1, 2000, and
December 31, 2018. Patients were included if they fulfilled all of the following inclusion criteria: (1)

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

older than 18 years; (2) diagnosis of atherosclerotic cardiovascular disease (ASCVD), diabetes, or an
LDL cholesterol level of 190 mg/dL or more; (3) at least 2 primary care encounters prior to study
entry; (4) no record of statin therapy prior to study entry; (5) an LDL cholesterol level of 100 mg/dL
or more prior to study entry; and (6) at least 1 LDL cholesterol measurement obtained 12 months or
more after study entry. Patients were excluded from analysis if they had missing demographic
information or had a record of an adverse reaction to a statin prior to the first record of statin therapy.

Exposures
A patient was entered into the study on the first date that statin therapy was recommended by a
health care professional. This was defined as the earliest of (1) the first record of statin therapy
(indicating initial acceptance of statin therapy by the patient) or (2) the first documented
nonacceptance of statin therapy by the patient. Patients exited the study on the first of the following:
(1) the date of death; (2) loss to follow-up as indicated by the absence of documentation from
primary care, cardiology, or endocrinology clinicians for greater than 12 months; or (3) December
31, 2018.

Outcome Measures
Acceptance or nonacceptance by the patient of a statin therapy recommendation by the health care
professional served as the primary independent variable. Acceptance of statin therapy was indicated
by a statin medication record in structured EHR data. Nonacceptance of statin therapy by the patient
was ascertained from clinician documentation in narrative EHR notes using NLP. Time to LDL
cholesterol control—time from study entry to the first measurement of an LDL cholesterol level of
less than 100 mg/dL—served as the primary outcome. Achievement of an LDL cholesterol level of
less than 100 mg/dL within 12 months of study entry was analyzed as a secondary outcome.

Data Acquisition
Information on baseline patient characteristics and study outcomes was obtained from the EHR at
Mass General Brigham. Information on participant race and ethnicity was based on self-report and
was also obtained from the EHR at Mass General Brigham. The following race and ethnicity categories
were obtained: Asian, Black, Hispanic, White, and other. The “other” category included American
Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and unknown. Natural language
processing tools to identify documented nonacceptance of statin therapy by patients were
developed using the publicly available Canary platform, version 2.01.21,22 Canary allows users to
create customized NLP tools by first defining groups of related words (word classes) that represent
subconcepts of interest (eg, statins) and then defining how these word classes can come together
(eg, nonacceptance of statin therapy) to describe the concept being sought. They were validated
against manual annotations of 3999 randomly selected clinician notes by 2 independent reviewers
whose ratings were subsequently reconciled. Additional details of development and validation of the
NLP tool can be found in eFigure 2 and eAppendices 1-3 in Supplement 1. To identify patients who
did not accept statin therapy, all EHR notes from clinicians in all specialties written between the date
of the first eligible diagnosis and the earliest date of the first record of statin therapy, the first record
of statin intolerance, or the date of study exit were analyzed.

Statistical Analysis
An individual patient served as the unit of analysis. Univariate analyses were conducted using the t
test for continuous variables and the χ2 test for categorical variables. The log-rank test was used to
compare time to LDL cholesterol control between patients who initially accepted statin therapy vs
patients who did not accept statin therapy.
A marginal Cox proportional hazards regression model was used to estimate the association
between statin therapy acceptance vs nonacceptance and time to LDL cholesterol control while
accounting for clustering within individual clinicians and adjusting for demographic confounders

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(age, sex, race and ethnicity, primary language, marital status, health insurance, and median income
by zip code), the Charlson Comorbidity Index, indication for statin therapy (ASCVD, diabetes, or LDL
cholesterol ⱖ190 mg/dL), family history of ASCVD or diabetes, ezetimibe use, year of the statin
therapy recommendation, and the baseline LDL cholesterol level. We also conducted a sensitivity
analysis (results in eAppendix 4 and eFigure 3 in Supplement 1) of how possible errors of the NLP
algorithm could affect the results of this analysis.
To study the factors associated with statin therapy acceptance, a multivariable logistic
regression model was constructed to estimate the association between statin therapy acceptance
and patient characteristics while accounting for clustering within individual clinicians. Interpretation
of P values was adjusted for multiple hypothesis testing using the Simes-Hochberg method.23,24
Analyses were performed using SAS, version 9.4 (SAS Institute Inc) and R, version 4.2.0 (R Group for
Statistical Computing) for Monte Carlo simulations. All P values were from 2-sided tests and results
were deemed statistically significant at P < .05.

Results
Natural Language Processing
We first sought to construct and evaluate the effectiveness of the NLP algorithm to identify patients
not accepting of statin therapy. In the course of the evaluation of the NLP algorithm, of the 3999
notes in the validation set, 40 contained documentation of a patient not accepting a statin. The
Cohen κ coefficient for interrater agreement between the 2 annotators was 0.872 (95% CI, 0.800-
0.945). The NLP tool used in the analysis achieved a sensitivity of 87.5% (95% CI, 73.2%-95.8%), a
specificity of 99.8% (95% CI, 99.5%-99.9%), and a positive predictive value of 77.8% (95% CI,
65.1%-86.8%).

Study Cohort
A total of 25 197 statin-naive adults at high cardiovascular risk followed up in primary care settings,
with both elevated baseline LDL cholesterol and follow-up LDL cholesterol measurements recorded,
were identified. After excluding patients who (1) had a record of an adverse effect to a statin prior to
the first record of statin therapy or (2) were missing data on age, sex, or median income by zip code,
24 212 patients (mean [SD] age, 58.8 [13.0] years; 12 294 women [50.8%]) were included in the
study (Table 1; eFigure 1 in Supplement 1). A total of 4 575 430 EHR notes were analyzed with NLP to
identify instances of statin nonacceptance by patients and their subsequent dates of study entry.
A total of 11 667 patients (48.2%) had ASCVD, and the rest had either diabetes or severe
hypercholesterolemia; 5584 patients (23.1%) had multiple indications for statin therapy. Among
study patients, 5308 (21.9%) initially did not accept statin therapy, and 1457 (6.0%) never initiated a
statin during the follow-up period. Women were more likely than men to both not accept the initial
statin therapy recommendation (24.1% [2957 of 12 294] vs 19.7% [2351 of 11 918]; P < .001) and never
initiate a statin during the study (7.2% [881 of 12 294] vs 4.8% [576 of 11 918]; P < .001). Similar
findings were observed in every subgroup in the analysis stratified by comorbidities (Figure 1).
Ezetimibe use was uncommon among patients who did not accept statin therapy and was similar
among women (44 of 2957 [1.5%]) and men (34 of 2351 [1.4%]) (P > .99). The median baseline LDL
cholesterol level was 137 mg/dL. Over the mean (SD) follow-up of 7.9 (4.5) years, 18 796 patients
(77.6%) reached an LDL cholesterol level of less than 100 mg/dL after a median of 1.9 years (IQR,
0.5-6.8 years).

Nonacceptance of Statin Therapy and LDL Cholesterol Control

Patients who accepted a statin therapy recommendation achieved an LDL cholesterol level of less
than 100 mg/dL after a median of 1.5 years (IQR, 0.4-5.5 years) compared with 4.4 years (IQR, 1.3-11.1
years) (Figure 2) for patients who did not (P < .001). In a multivariable analysis adjusted for patients’
demographic characteristics and comorbidities, nonacceptance of statin therapy was associated with

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

longer time to achieve LDL cholesterol control (hazard ratio [HR], 0.57 [95% CI, 0.55-0.60];
P < .001) (Table 2). Female sex was an independent risk factor associated with a longer time to
achieve LDL cholesterol control (HR, 0.84 [95% CI, 0.81-0.87]; P < .001). A higher baseline LDL

Table 1. Baseline Characteristics of Study Patients

Patients, No. (%)

Characteristic Female (n = 12 294) Male (n = 11 918) P value
Age, mean (SD), y 60.7 (12.9) 56.8 (13.0) <.001
Study entry year, mean (SD)a 9.4 (4.8) 9.7 (4.7) <.001
Baseline LDL cholesterol, mean (SD), mg/dL 149.0 (37.9) 143.3 (35.5) <.001
Income (in the $10 000s), mean (SD)b 6.9 (2.5) 7.2 (2.7) <.001
Charlson Comorbidity Index, mean (SD) 5.2 (3.8) 4.6 (4.0) <.001
No. of drug allergies, mean (SD) 2.8 (3.4) 1.3 (1.9) <.001
Days of follow-up, mean (SD) 2930.3 (1668.7) 2793.6 (1632.5) <.001
English speaking 10 321 (84.0) 10 480 (87.9) <.001
Married 5269 (42.9) 7435 (62.4) <.001
Government insurance 5557 (45.2) 4392 (36.9) <.001
Smoker 4195 (34.1) 4523 (38.0) <.001
Ezetimibe use 267 (2.2) 279 (2.3) .38
CAD 3989 (32.5) 4770 (40.0) <.001
CVA 1915 (15.6) 1667 (14.0) <.001
PVD 1796 (14.6) 1590 (13.3) .004
Diabetes 6206 (50.5) 5793 (48.6) .004
LDL cholesterol ≥190 mg/dL 4216 (34.3) 3340 (28.0) <.001 Abbreviations: CAD, coronary artery disease; CVA,
Family history of diabetes 3230 (26.3) 2637 (22.1) <.001 cerebrovascular accident; CVD, cardiovascular disease;
Family history of CVD 2446 (19.9) 1963 (16.5) <.001 LDL, low-density lipoprotein; PVD, peripheral
vascular disease.
Race and ethnicity
SI conversion factor: To convert LDL cholesterol to
Asian 539 (4.4) 499 (4.2)
millimoles per liter, multiply by 0.0259.
Black 1163 (9.5) 905 (7.6) a
After study start in 2000.
Hispanic 770 (6.3) 675 (5.7) <.001 b
Mean annual household income by zip code.
White 8758 (71.2) 8907 (74.7)
c
Included American Indian or Alaska Native, Native
Otherc 1064 (8.7) 932 (7.8)
Hawaiian or Other Pacific Islander, and unknown.

Figure 1. Sex Differences in Statin Acceptance

0.30
Women Men

0.25
Proportion of patients not accepting statins

0.20

0.15

0.10

0.05
Error bars indicate standard error. ASCVD indicates
atherosclerotic cardiovascular disease; CAD, coronary
artery disease; CVA, cerebrovascular accident; LDL,
0
ASCVD No CAD No CVA No PVD No Diabetes No High No high low-density lipoprotein; and PVD, peripheral
ASCVD CAD CVA PVD Diabetes LDL LDL
cholesterol cholesterol vascular disease.

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

cholesterol level was also associated with a longer time to achieve LDL cholesterol control, while a
higher Charlson Comorbidity Index, a history of diabetes or stroke, and a later study entry year were
associated with a shorter time to achieve LDL cholesterol control.

Figure 2. Statin Acceptance and Time to Low-Density Lipoprotein (LDL) Cholesterol Control

100

Statin accepted
Patients achieving LDL cholesterol <100 mg/dL, %

80

Statin not accepted

60

40

20

0
0 1000 2000 3000 4000 5000
The last 5% of the population in each group were not
Time since initial statin recommendation, d included in the plot due to low participant numbers
No. at risk
Statin accepted 18 904 6585 3580 2011 968
and resulting wide 95% CIs. To convert LDL cholesterol
Statin not accepted 5308 2874 1665 912 439 to millimoles per liter, multiply by 0.0259.

Table 2. Patient Characteristics and Time to LDL Cholesterol Control

Parameter Hazard ratio (95% CI)a P value

Age 1.01 (1.01-1.01) <.001
Study entry year 1.02 (1.02-1.03) <.001
Baseline LDL cholesterol (per 10 mg/dL) 0.94 (0.94-0.95) <.001
Median household income by zip code (per $10 000) 0.98 (0.97-0.99) <.001
Charlson Comorbidity Index 1.02 (1.02-1.03) <.001
No. of drug allergies 0.98 (0.98-0.99) <.001
English as the primary language 0.95 (0.90-1.00) .06
Married 1.02 (0.99-1.06) .16
Government insurance 1.00 (0.97-1.03) .91
Smoker 1.02 (0.98-1.05) .31
Ezetimibe use 0.92 (0.84-1.02) .13
CAD 0.99 (0.95-1.02) .44 Abbreviations: CAD, coronary artery disease; CVA,
CVA 1.10 (1.06-1.15) <.001 cerebrovascular accident; CVD, cardiovascular disease;
PVD 1.05 (1.00-1.09) .045 LDL, low-density lipoprotein; PVD, peripheral
vascular disease.
Diabetes 1.21 (1.16-1.26) <.001
a
Marginal Cox proportional hazards regression model
History of LDL cholesterol ≥190 mg/dL 0.70 (0.67-0.74) <.001
was used to estimate the association between statin
Family history of diabetes 1.00 (0.97-1.04) .85 therapy acceptance vs nonacceptance and time to
Family history of CVD 0.97 (0.93-1.01) .09 LDL cholesterol control while accounting for
Race and ethnicityb clustering within individual clinicians. All variables in
Asian 1.05 (0.96-1.15) .30 the table were included in the model.
b
Black 0.82 (0.78-0.87) <.001 White race served as the reference (comparison)
category.
Hispanic 0.86 (0.79-0.95) .002
c
Included American Indian or Alaska Native, Native
Otherc 0.94 (0.89-1.00) .06
d
Hawaiian or Other Pacific Islander, and unknown.
Female 0.84 (0.81-0.87) <.001
d
Male biological sex served as the reference
Statin nonacceptance 0.57 (0.55-0.60) <.001
(comparison) category.

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

In a secondary analysis, 42.1% (7955 of 18 904) of patients who did accept statin therapy vs
21.0% (1114 of 5308) of patients who did not accept statin therapy achieved an LDL cholesterol level
of less than 100 mg/dL within 12 months (P < .001). In multivariable analysis, nonacceptance of statin
therapy was associated with an odds ratio (OR) for achieving LDL cholesterol control within 12
months of 0.32 (95% CI, 0.30-0.35) (P < .001); findings of a secondary analysis using LDL decrease
by 50% as the outcomes were similar (eAppendix 5 in Supplement 1). Women (independently from
other characteristics) were less likely to achieve LDL cholesterol control within 12 months (OR, 0.85
[95% CI, 0.80-0.90]; P < .001).

Factors Associated With Statin Therapy Acceptance

In multivariable analysis (Figure 3), women were less likely to agree to take a statin when first
recommended by a clinician (OR, 0.82 [95% CI, 0.78-0.88]; P < .001). Presence of cardiovascular
disease, higher baseline LDL cholesterol, and history of smoking were associated with a greater
probability of statin acceptance. All of these associations were statistically significant after
adjustment for multiple hypothesis testing.

Discussion
In this large, population-based cohort study, we found that many patients with unequivocal
indications for cholesterol lowering did not accept statin therapy recommended to them by their
health care professionals. These patients were subsequently less likely to achieve LDL cholesterol
control within 1 year and took significantly longer to reach it compared with patients who initiated
statins. Women had lower rates of statin acceptance than men, potentially contributing to the known
sex disparities in LDL cholesterol control. These findings shed light on an important and previously
unexamined aspect of prevention of cardiovascular disease.

Figure 3. Patient Characteristics and Acceptance of Statin Therapy Recommendation

Lower odds Higher odds

of statin of statin
Characteristic OR (95% CI) acceptance acceptance
English as primary language 0.70 (0.63-0.79)
Female 0.82 (0.78-0.88)
White 0.94 (0.87-1.02)
Family history of CVD 0.97 (0.90-1.05)
Government insurance 0.97 (0.92-1.03)
Married 0.98 (0.92-1.03)
Number of drug allergies 0.99 (0.98-1.00)
Baseline LDL cholesterol, per 10 mg/dL 1.00 (0.99-1.01)
Age 1.00 (1.00-1.00)
Income, per $10 000 1.00 (0.99-1.01)
CCI score 1.01 (1.00-1.02)
Family history of diabetes 1.01 (0.94-1.09)
Study entry year 1.01 (1.00-1.03)
PVD 1.07 (0.98-1.17)
History of smoking 1.11 (1.05-1.19)
Diabetes 1.14 (1.07-1.22)
CAD 1.24 (1.15-1.33)
LDL cholesterol ≥190 mg/dL 1.25 (1.15-1.35)
CVA 1.26 (1.15-1.37)

0.6 0.8 1.0 1.2 1.4 1.6

OR (95% CI)

A multivariable logistic regression model that included all variables in the figure was indicates Charlson Comorbidity Index; CAD, coronary artery disease; CVA,
constructed to estimate the association between statin therapy acceptance and patient cerebrovascular accident; CVD, cardiovascular disease; OR, odds ratio; and PVD,
characteristics while accounting for clustering within individual clinicians. To convert peripheral vascular disease.
low-density lipoprotein (LDL) cholesterol to millimoles per liter, multiply by 0.0259. CCI

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

Nonacceptance of statin therapy recommendations is in many ways distinct from the more
widely studied phenomenon of statin nonadherence. Unlike medication nonadherence, which is
often due to high medication costs or adverse reactions the patient developed,25-27 nonacceptance
of treatment recommendations takes place before the patient has had any direct experience with the
medication; the reasons for it are therefore likely to be different. Many measures of the quality of
cardiovascular care may interpret patient nonacceptance of statin therapy as “nonprescriptions” due
to lack of appropriate action by the health care professional.28,29 This study demonstrates that
patients are active agents in their care, and their preferences and priorities should be carefully taken
into account when making treatment recommendations.30,31
Debates continue about indications for statin therapy for patients with low cardiovascular risk
or for the primary prevention population.32-34 However, the present study identified high rates of
nonacceptance of statin therapy among patients at high cardiovascular risk: those with existing
ASCVD, diabetes, or an LDL cholesterol level of 190 mg/dL or more. These are vulnerable individuals
for whom evidence-based cholesterol-lowering therapy could significantly lower the incidence of
cardiovascular events and related morbidity and mortality. Therefore, the findings of this study have
significant implications for public health as we continue to strive to decrease the risks of ASCVD—the
number one cause of death in the US and worldwide.35,36
Acceptance of a statin therapy recommendation was found to be associated with achievement
of LDL cholesterol control. This association is not as self-evident as it may seem because patients’
cholesterol levels may have been associated with many other factors. On the one hand, a patient’s
initial acceptance of statin therapy does not necessarily guarantee continuous use of the statin, or
even any use at all, because patients can often be nonadherent to statins.37,38 On the other hand, a
patient’s initial nonacceptance does not necessarily indicate that the patient will never take a statin—
nearly two-thirds of patients who initially did not accept a statin did eventually start taking statins,
which may have occurred shortly after their initial nonacceptance. Finally, both groups of patients
may have also elected to use other nonstatin cholesterol-lowering medications, such as ezetimibe, or
implemented lifestyle changes that may lead to lower cholesterol levels. However, the association
of statin nonacceptance with LDL cholesterol levels was marked despite these potential
considerations.
The present study identified significant sex disparities in the acceptance of statin therapy.
Women were more than 20% more likely than men not to accept their clinician’s initial statin therapy
recommendation; similar findings were observed among patients with known coronary artery
disease and all other comorbidity subgroups. This disparity increased as time went on; over the entire
course of the study, women were 50% more likely to never initiate statins. Multiple previous studies
have reported lower rates of cholesterol control among women compared with men.39-41 These
differences have been explained in part by sex disparities in the rates of adherence and adverse
effects to statins.13,42-44 The present study suggests that disparities in nonacceptance of a statin
therapy recommendation are another important factor; further research is needed to assess why
women at high cardiovascular risk are less likely to accept their clinicians’ recommendation of
statin therapy.
A distinct aspect of this study was the use of novel NLP technology to identify patients who did
not accept a statin therapy recommendation by their clinician. Nonacceptance of statin therapy by
patients is typically documented only in narrative clinician notes because EHR systems do not usually
have checkboxes, drop-down lists, or other structured data elements where it could be recorded.
Data analysis for the study involved over 4 million electronic clinician notes, rendering traditional
manual medical record review infeasible. On the other hand, the validated NLP tool developed for
the purpose of this study processed this massive amount of data within days. This study therefore
highlights the potential for the use of artificial intelligence technology in combination with vast data
sets to make novel research questions accessible for investigation for the first time.

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

Strengths and Limitations

The present study has several strengths. To our knowledge, this is the first population-based study
that examined nonacceptance of statin therapy recommendations by patients. It included a large
population of patients treated in primary care settings, similar to most patients with
hypercholesterolemia in the US. The study focused on patients with unequivocal indications for
statin therapy, making its findings critical for the prevention of cardiovascular events among this
high-risk population. Finally, the use of artificial intelligence NLP technology allowed for a unique
viewpoint into a previously minimally explored aspect of the treatment of hypercholesterolemia.
Study findings should also be interpreted in light of its limitations. Its observational nature does
not allow for the identification of causal relationships. Some of the statin nonacceptance may not
have been documented in clinician notes, and other instances may not have been detected by the
NLP algorithm. Validation of the NLP algorithm was not stratified by biological sex, and it is possible
that the accuracy of the algorithm is different for female vs male patients. Only the first statin therapy
recommendation for each patient was examined; future studies should address whether similar
findings hold for multiple recommendations. Specific reasons for statin nonacceptance, discussion
of lifestyle changes, and association of clinician characteristics were not examined and should be
investigated in future research. Although a broad selection of potential confounding variables was
included in the multivariable analysis, other unknown confounders not accounted for may have
influenced the association between statin acceptance and LDL cholesterol control. In addition,
because our study cohort included only patients who were known to have obtained an LDL
cholesterol level measurement after a statin recommendation, it may be biased by the exclusion of
patients who did not return for follow-up care. Finally, the study population is composed of
encounters within a single-center health care system; the patient population therefore may not be
generalizable to other geographic or demographic cohorts.

Conclusions
In this cohort study, nonacceptance of a statin therapy recommendation was common among
patients at high cardiovascular risk and was associated with higher LDL cholesterol levels, potentially
translating into an increased incidence of cardiovascular events. Nonacceptance of statins was
particularly prevalent among women, possibly contributing to the known sex disparities in treatment
of high cholesterol. Further research is needed to identify the reasons why patients do not accept
statin therapy recommendations and the reasons for the higher rates of this important clinical
phenomenon among women.

ARTICLE INFORMATION
Accepted for Publication: December 30, 2022.
Published: February 28, 2023. doi:10.1001/jamanetworkopen.2023.1047
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Brown CJ
et al. JAMA Network Open.
Corresponding Author: Alexander Turchin, MD, MS, Division of Endocrinology, Brigham and Women’s Hospital,
221 Longwood Ave, Boston, MA 02115 (aturchin@bwh.harvard.edu).
Author Affiliations: Division of Endocrinology, Brigham and Women’s Hospital, Boston, Massachusetts (Brown,
Chang, Hosomura, Malmasi, Morrison, Shubina, Turchin); Pharmacy Department, Tufts Medical Center, Boston,
Massachusetts (Brown); Harvard Medical School, Boston, Massachusetts (Chang, Hosomura, Malmasi, Lan,
Turchin); Amazon.com Inc, Seattle, Washington (Malmasi); Center for Clinical Investigation, Brigham and Women’s
Hospital, Boston, Massachusetts (Lan).
Author Contributions: Dr Turchin had full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Brown, Shubina, Turchin.

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 JAMA Network Open | Cardiology Sex Disparities in Nonacceptance of Statin Therapy and LDL Cholesterol Levels

Acquisition, analysis, or interpretation of data: Brown, Chang, Hosomura, Malmasi, Morrison, Lan, Turchin.
Drafting of the manuscript: Brown, Lan.
Critical revision of the manuscript for important intellectual content: Chang, Hosomura, Malmasi, Morrison,
Shubina, Lan, Turchin.
Statistical analysis: Brown, Shubina, Lan.
Obtained funding: Turchin.
Administrative, technical, or material support: Chang, Morrison.
Supervision: Turchin.
Conflict of Interest Disclosures: Dr Chang reported receiving grants from Novo Nordisk, Eli Lilly, Boehringer
Ingelheim, Applied Therapeutics, and Better Therapeutics outside the submitted work. Dr Turchin reported
receiving grants from AstraZeneca, Edwards, Eli Lilly, and Novo Nordisk; receiving personal fees from Covance and
Proteomics International; and has equity in Brio Systems outside the submitted work. No other disclosures were
reported.
Funding/Support: This study was funded in part by the Patient-Centered Outcomes Research Institute (contract
ME-2019C1-15328).
Role of the Funder/Sponsor: The funding source 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
decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.

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SUPPLEMENT 1.
eFigure 1. Patient Flow
eAppendix 1. Natural Language Processing Technology
eFigure 2. Screenshot of Canary Natural Language Processing Platform
eAppendix 2. Development of Natural Language Processing Tool for Identification of Statin Non-Acceptance by
Patients
eAppendix 3. Evaluation of Natural Language Processing Tools
eAppendix 4. Sensitivity Analysis of the Effect of Possible Errors Potentially Introduced by the NLP Algorithm
eFigure 3. Hazard Ratio Estimates Obtained by the NLP Accuracy Sensitivity Analysis
eAppendix 5. Secondary Analysis of 50% LDL Decrease at 12 Months

SUPPLEMENT 2.
Data Sharing Statement

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