Sex-Related Disparities in Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease

Michelle T Lee; Dhruv Mahtta; David J Ramsey; Jing Liu; Arunima Misra; Khurram Nasir; Zainab Samad; Dipti Itchhaporia; Safi U Khan; Richard S Schofield; Christie M Ballantyne; Laura A Petersen; Salim S Virani

doi:10.1001/jamacardio.2021.0683

. 2021 Apr 21;6(7):1–9. doi: 10.1001/jamacardio.2021.0683

Sex-Related Disparities in Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease

Michelle T Lee ^1,², Dhruv Mahtta ^1,^2,³, David J Ramsey ¹, Jing Liu ³, Arunima Misra ^4,³, Khurram Nasir ⁵, Zainab Samad ^4,⁶, Dipti Itchhaporia ⁷, Safi U Khan ⁸, Richard S Schofield ^9,¹⁰, Christie M Ballantyne ^3,¹¹, Laura A Petersen ^1,², Salim S Virani ^1,^3,^4,^✉

¹Health Policy, Quality and Informatics Program, Michael E. DeBakey VA Medical Center Health Services Research and Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas

²Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas

³Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas

⁴Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas

⁵Methodist DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, Texas

⁶Department of Medicine, The Aga Khan University, Karachi, Pakistan

⁷Department of Medicine, Cardiology Division, Hoag Memorial Hospital, University of California at Irvine

⁸Department of Medicine, West Virginia University, Morgantown

⁹Division of Cardiovascular Medicine, University of Florida, Gainesville

¹⁰Department of Veterans Affairs Medical Center, Gainesville, Florida

¹¹Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas

^✉

Corresponding Author: Salim S. Virani, MD, PhD, Health Services Research and Development (152), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd, Houston, TX 77030 (virani@bcm.edu).

Accepted for Publication: February 16, 2021.

Published Online: April 21, 2021. doi:10.1001/jamacardio.2021.0683

Author Contributions: Drs Lee and Virani 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: Lee, Mahtta, Nasir, Samad, Petersen, Virani.

Acquisition, analysis, or interpretation of data: Lee, Ramsey, Liu, Misra, Itchhaporia, Khan, Schofield, Ballantyne, Virani.

Drafting of the manuscript: Lee, Schofield.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ramsey.

Obtained funding: Virani.

Administrative, technical, or material support: Liu, Itchhaporia, Petersen, Virani.

Supervision: Mahtta, Schofield, Petersen, Virani.

Conflict of Interest Disclosures: Dr Nasir reported serving on the advisory boards of Amgen, Novartis, and the Medicines Company; and his research is partly supported by the Jerold B. Katz Academy of Translational Research. Dr Ballantyne reported grants from Abbott Diagnostic, Akcea, Amgen, Esperion, Novartis, Regeneron, Roche Diagnostic, the National Institutes of Health, American Heart Association, and the American Diabetes Association and grant/research support and personal fees from Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, Astra Zeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma Inc, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo outside the submitted work. Dr Virani reported grants from the US Department of Veterans Affairs, World Heart Federation, Tahir, and Jooma Family Research Grant during the conduct of the study and other support from the American College of Cardiology Honorarium in his role as the Associate Editor for Innovations ACC.org outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by a US Department of Veterans Affairs Health Services Research and Development Service Investigator Initiated Grant (IIR 16–072), an American Heart Association Beginning Grant-in-Aid (14BGIA20460366), the American Diabetes Association Clinical Science and Epidemiology award (1-14-CE-44), and the Houston VA Health Services Research and Development Center for Innovations grant (CIN13-413).

Role of the Funder/Sponsor: The funding sources 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.

Disclaimer: The opinions expressed reflect those of the authors and not necessarily those of the US Department of Veterans Affairs or the US government.

^✉

Corresponding author.

PMCID: PMC8060887 PMID: 33881448

Key Points

Question

In young patients with premature atherosclerotic cardiovascular disease (ASCVD), how are sex-based differences associated with use of antiplatelets and statins?

Findings

In this cross-sectional study, women veterans with premature ASCVD (≤55 years) and extremely premature ASCVD (≤40 years) were less likely to receive antiplatelet agents or statins than men. Additionally, women with premature ischemic heart disease were comparatively less statin adherent.

Meaning

In this study, women veterans with premature and extremely premature ASCVD received poorer secondary prevention care; hence, a systematic approach toward health care delivery improvement and patient education is necessary to narrow this health care disparity for women.

Abstract

Importance

There is a paucity of data regarding secondary prevention care disparities in women with premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), defined as an ASCVD event at 55 years or younger and 40 years or younger, respectively.

Objective

To evaluate sex-based differences in antiplatelet agents, any statin, high-intensity statin (HIS) therapy, and statin adherence in patients with premature and extremely premature ASCVD.

Design, Setting, and Participants

This was a cross-sectional, multicenter, nationwide VA health care system–based study with patients enrolled in the Veterans With Premature Atherosclerosis (VITAL) registry. The study assessed patients who had at least 1 primary care visit in the Veterans Affairs (VA) health care system from October 1, 2014, to September 30, 2015. Participants included 147 600 veteran patients with premature ASCVD, encompassing ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and peripheral arterial disease (PAD).

Exposures

Women vs men with premature and extremely premature ASCVD.

Main Outcomes and Measures

Antiplatelet use, any statin use, HIS use, and statin adherence (proportion of days covered [PDC] ≥0.8).

Results

We identified 10 413 women and 137 187 men with premature ASCVD (age ≤55 years) and 1340 women and 8145 men with extremely premature (age ≤40 years) ASCVD. Among patients with premature and extremely premature ASCVD, women represented 7.1% and 14.1% of those groups, respectively. When compared with men, women with premature ASCVD had a higher proportion of African American patients (36.1% vs 23.8%) and lower proportions of Asian patients (0.5% vs 0.7%) and White patients (56.1% vs. 68.1%). In the extremely premature ASCVD group, women had a comparatively higher proportion of African American patients (36.8% vs 23.2%) and lower proportion of White patients (55.0% vs 67.8%) and Asian patients (1.3% vs 1.5%) than men. Among patients with premature IHD, women received less antiplatelet (adjusted odds ratio [AOR], 0.47, 95% CI, 0.45-0.50), any statin (AOR, 0.62; 95% CI, 0.59-0.66), and HIS (AOR, 0.63; 95% CI, 0.59-0.66) therapy and were less statin adherent (mean [SD] PDC, 0.68 [0.34] vs 0.73 [0.31]; β coefficient: −0.02; 95% CI, −0.03 to −0.01) compared with men. Similarly, women with premature ICVD and premature PAD received comparatively less antiplatelet agents, any statin, and HIS. Among patients with extremely premature ASCVD, women also received less antiplatelet therapy (AOR, 0.61; 95% CI, 0.53-0.70), any statin therapy (AOR,0.51; 95% CI, 0.44-0.58), and HIS therapy (AOR, 0.45; 95% CI, 0.37-0.54) than men. There were no sex-associated differences in statin adherence among patients with premature ICVD, premature PAD, or extremely premature ASCVD.

Conclusions and Relevance

This cross-sectional study revealed that women veterans with premature ASCVD and extremely premature ASCVD receive less optimal secondary prevention cardiovascular care in comparison with men. Women with premature ASCVD, particularly those with IHD, were also less statin adherent. Multidisciplinary and patient-centered interventions are needed to improve these disparities in women.

This study evaluates sex-based differences in antiplatelet agents, any statin, high-intensity statin therapy, and statin adherence in patients with premature and extremely premature atherosclerotic cardiovascular disease.

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide.¹ To curb this trend, international multidisciplinary task forces developed practice guidelines. In particular, secondary prevention guidelines recommend initiating antiplatelet and statin therapy after an ASCVD event, defined as ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), or peripheral arterial disease (PAD).^2,3,4,5 Although men and women derive equal benefit from secondary prevention,^6,7,8 cardiovascular care disparities persist between the sexes.^9,10 Moreover, women with premature ASCVD have comparatively higher mortality rates than men.¹¹

Especially in young patients with ASCVD, secondary prevention optimization is imperative for reducing disease burden, psychosocial effects, and financial costs for the patient, their caretakers, and the health care system.¹² However, there is a paucity of data comparing secondary prevention between men and women with premature (≤55 years) and extremely premature ASCVD (≤40 years). In our analyses, we evaluated sex-based differences in antiplatelet use, any statin and high-intensity statin (HIS) therapy, and statin adherence among patients with premature and extremely premature ASCVD.

Methods

The institutional review board at Baylor College of Medicine approved our study protocols, which did not involve patient interaction or include identifiable patient data. For this reason, patient consent was not required. Our study abided by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.¹³

We conducted a retrospective cohort study using the national Veterans Affairs (VA) electronic medical record (EMR) system and clinical data sets during the fiscal year 2015. Included patients with premature and extremely premature ASCVD received care from at least 1 of 130 VA facilities or associated community-based outpatient clinics. Using diagnostic codes for IHD, ICVD, or PAD, as established by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Current Procedural Terminology (CPT), we identified 1 248 158 patients 18 years and older with ASCVD. We included patients with at least 2 outpatient diagnosis codes for ASCVD or 1 procedural code for percutaneous intervention or surgical bypass grafting.^14,15 From this patient pool, 200 medical records were randomly selected and manually reviewed for ASCVD diagnosis accuracy. This medical record review demonstrated that our code-based approach had a 95% positive predictive value of correctly identifying ASCVD. Next, we created the Veterans With Premature Atherosclerosis (VITAL) nationwide registry based on age cutoff parameters.^16,17,18 Patients with an ASCVD event at 55 years or younger and 40 years or younger were included in the premature ASCVD and extremely premature ASCVD cohorts, respectively. We excluded patients without documented birth date or sex and those with limited life expectancy, defined by metastatic cancer within 5 years or hospice care within 12 months.¹⁹

For each ASCVD subtype (IHD, ICVD, and PAD), we created 3 phenotypes using ICD-9-CM and CPT codes.^16,17,18 Phenotype categorization entailed dividing IHD into acute coronary syndrome, chronic coronary artery disease, and coronary revascularization; ICVD into transient ischemic attack or stroke, and cerebral revascularization; and PAD into intermittent claudication, peripheral arterial occlusion, and peripheral revascularization (eTable 1 in the Supplement).

For all patients, we obtained demographic data, including age, sex, race/ethnicity, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Using ICD-9-CM and CPT codes, we identified concomitant hypertension, type 2 diabetes, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD). Additionally, we assessed low-density lipoprotein cholesterol (LDL-C) levels, statin-associated adverse effects (SAAEs), and Medicaid coverage. We ascertained SAAE presence by accessing the VA adverse drug event reporting system (ADERS), a voluntary postmarketing surveillance system used by VA clinicians.²⁰ Medicaid status was defined by active coverage within 1 year before or after the index PCP visit. Diagnosis Cost Group Relative Risk Score (DCG-RRS) calculations assessed each patient’s overall illness burden. A DCG-RRS score of 1 indicates an average illness burden; scores less than or greater than 1 denotes lower-than-average or higher-than-average illness burden, respectively.^21,22 Facility- and clinician-level variables included care provided by physician vs advanced practice clinician (APC; nurse practitioner or physician assistant), receipt of care at a teaching vs nonteaching facility, and location at urban vs rural facility. The most recent primary care provider (PCP) visit in fiscal year 2015 represented the index visit. From this reference point, we calculated the median number of PCP visits and percentage of patients receiving cardiology visits in the 12 months preceding the index visit.

Primary outcomes included antiplatelet use, any statin and HIS therapy, and statin adherence among patients with premature and extremely premature ASCVD. Use for this study’s purpose referred to a medication prescribed up to 100 days prior to or 14 days after the patient’s index PCP visit, in efforts to capture treatment outside of the PCP appointment date, as shown in prior studies.^23,24,25 We included VA and non-VA prescriptions, provided that such medications were documented accordingly in the EMR. Antiplatelet, statin (atorvastatin, rosuvastatin, pravastatin, fluvastatin, lovastatin, simvastatin, and pitavastatin), and HIS use were obtained by VA pharmacy records. Antiplatelet use included patients with active prescriptions of aspirin, ticagrelor, clopidogrel, prasugrel, or ticlopidine. Those prescribed anticoagulants (warfarin, rivaroxaban, apixaban, dabigatran, and enoxaparin) were removed from the denominator of antiplatelet use calculations, thus excluded from antiplatelet use analysis. The HIS referred to prescriptions of atorvastatin, at least 40 mg, or rosuvastatin, at least 20 mg, consistent with the American Heart Association/American College of Cardiology cholesterol guidelines.⁵ Statin adherence was assessed by using the previously described and validated measurement of proportion of days covered (PDC), calculated by taking the prescription refill’s covered days supply divided by total days in a given period.^22,26 These calculations took into account early refills, changes in statin dosages, and statin switching. For dose changes, we assumed pill-splitting or doubling of pills from previous prescriptions. Switching of statins presupposed wasting the remainder of previous medication and initiation of newly prescribed statin. Stockpiling and early refills were addressed by starting the newly refilled medication’s covered days’ supply after completion of previous refill. We analyzed PDC as a categorical variable (≥0.8 or <0.8) and continuous variable. Adherence in this context represented patient request for and pharmacy fulfillment of medication fills. We applied the reference value of PDC ≥0.8 as indication of statin adherence, similar to studies detailing accepted medication adherence measurement.²⁷

Categorical and continuous variables were compared between sexes using χ² tests and t tests, respectively. We compared antiplatelet, any statin and HIS use, and statin adherence between men and women with premature and extremely premature ASCVD. Multivariable regression assessed the association between female sex and antiplatelet use, any statin and HIS use, and statin adherence (using PDC as a continuous variable and as PDC ≥0.8). For all analyses, male sex acted as the referent category. Variables adjusted for in regression analyses included patient’s age, race/ethnicity, type of ASCVD (IHD vs ICVD or PAD), obesity, hypertension, diabetes, MDD and/or PTSD, SAAE, Medicaid coverage, DCG-RRS, clinician type (physician vs APC), teaching facility (vs nonteaching facility), urban facility (vs rural facility), number of cardiology visits 12 months prior to index PCP visit, and number of PCP visits 12 months prior to index PCP visit.

Further evaluation of the premature ASCVD cohort involved outcome analyses (antiplatelet use, statin use, HIS use, and statin adherence) of each subtype (IHD, ICVD, and PAD). In addition to the previously listed adjustments, we also adjusted for ASCVD subtypes accordingly. For example, regression analysis for premature ICVD included adjustments for ICVD only vs ICVD+IHD vs ICVD+PAD vs ICVD+PAD+IHD. Because Lehavot et al²⁸ previously demonstrated that female VA patients are more likely Black, have MDD/PTSD, and have low socioeconomic status (SES), our analyses included adjustments for race/ethnicity, MDD/PTSD, and Medicaid status. Additionally, we performed interaction testing using variables of female sex and Black race. Statistical analysis was performed using SAS, version 9.1.3 (SAS Institute), and Stata, version 14 (StataCorp). The P value level of significance was less than .05, and the P value was 2-sided.

Results

We identified 1 248 287 patients with ASCVD. Using age-based exclusion criteria, our analytic cohort included 147 600 patients (10 413 women and 137 187 men) with premature ASCVD (Table 1; eFigure 1 in the Supplement). In this group, women were younger (mean age, 48.0 years) than men (49.9 years). Among women, compared with men, there was a higher proportion of African American patients (36.1% [n = 3762] vs 23.8% [n = 32 628]) and lower proportions of Asian patients (0.5% [n = 55] vs 0.7% [n = 1001]) and White patients (56.1% [n = 5840] vs 68.1% [n = 99 484]). Notably, women had a higher prevalence of ICVD (41.8% [n = 4355] vs 26.2% [n = 35 964]) and MDD and/or PTSD (54.8% [n = 5711] vs 38.4% [n = 52 681]) than men. However, women were less likely to be obese (BMI ≥30, 54.5% [n = 5677] vs 55.4% [n = 76 021]) or have a history of hypertension (88.0% [n = 9160] vs 94.7% [n = 129 913]), diabetes (37.8% [n = 3931] vs 49.5% [n = 67 930]), IHD (60.8% [n = 6332] vs 80.4% [n = 110 329]), or PAD (9.8% [n = 1022] vs 13.2% [n = 18 036]). Lastly, compared with men, women had comparatively higher LDL-C levels (155 mg/dL vs 149.2 mg/dL; to convert to millimoles per liter, multiply by 0.0259).

Table 1. Baseline Characteristics of Patients With Premature Atherosclerotic Cardiovascular Disease.

Characteristics	Age 18-55 y with premature ASCVD, No. (%)		P value
Characteristics	Women (n = 10 413)	Men (n = 137 187)	P value
Demographics
Age, mean (SD), y	48.0 (6.55)	49.9 (5.21)	<.001
Race/ethnicity
Asian	55 (0.5)	1001 (0.7)	<.001
African American	3762 (36.1)	32 628 (23.8)	<.001
White	5840 (56.1)	93 484 (68.1)	<.001
Medical history
BMI ≥30	5677 (54.5)	76 021 (55.4)	.08
Hypertension	9160 (88.0)	129 913 (94.7)	<.001
Diabetes	3931 (37.8)	67 930 (49.5)	<.001
Ischemic heart disease	6332 (60.8)	110 329 (80.4)	<.001
Ischemic cerebrovascular disease	4355 (41.8)	35 964 (26.2)	<.001
Peripheral arterial disease	1022 (9.8)	18 036 (13.2)	<.001
LDL-C, mean (SD), mg/dL	155.0 (45.71)	149.2 (43.38)	<.001
MDD and/or PTSD	5711 (54.8)	52 681 (38.4)	<.001
Statin-associated adverse effects	1278 (12.3)	16 094 (11.7)	.10
Overall health status and health care use
Diagnostic cost group relative risk score, mean (SD)	2.4 (2.54)	2.1 (2.59)	<.001
Medicaid insurance	461 (4.4)	6518 (4.8)	.13
Facility-level and clinician-level characteristics
Receiving care at a teaching facility	5428 (52.1)	62 930 (45.9)	<.001
Physician PCP	7593 (72.9)	107 425 (78.3)	<.001
Receiving care at rural facility	1205 (11.6)	21 201 (15.5)	<.001
Patients with a PCP visit in the 12 mo prior to the index PCP visit	10 044 (96.5)	129 951 (94.7)	<.001
Patients with a cardiology visit in the 12 mo prior to the index PCP visit	2362 (22.7)	38 115 (27.8)	<.001
No. of PCP visits in the 12 mo prior to the index PCP visit, median (IQR)	7.0 (6.41)	5.5 (5.51)	<.001

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Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; MDD, major depressive disorder; PCP, primary care provider; PTSD; posttraumatic stress disorder.

SI conversion factor: To convert cholesterol levels to millimoles per liter, multiply by 0.0259.

Adjusted regression analyses showed that women with premature ASCVD, compared with men, were significantly less likely to receive antiplatelets (61.3% vs 79.2%; odds ratio [OR], 0.59; 95% CI, 0.56-0.61), any statin (57.5% vs 75.1%; OR, 0.66; 95% CI, 0.63-0.69), or HIS therapy (23.5% vs 38.1%; OR, 0.64; 95% CI, 0.60-0.67). Women were also less statin adherent than men (mean [SD], 0.67 [0.35] vs 0.72 [0.32]; β coefficient, −0.01; 95% CI, −0.02 to −0.01) than men (eTable 2 in the Supplement; Figure).

Further analysis of premature ASCVD entailed separating patients into their respective ASCVD subtypes of IHD, ICVD, and PAD (eTable 3 in the Supplement). Among patients with premature IHD, women were less likely than men to receive antiplatelet (64.0% vs 82.5%; OR, 0.47; 95% CI, 0.42-0.47), any statin (63.1% vs 78.4%; OR, 0.57; 95% CI, 0.54-0.61), or HIS therapy (28.7% vs 41.8%; OR, 0.61; 95% CI, 0.58-0.65; Table 2). Women with premature IHD were also less statin adherent (mean [SD], 0.68 [0.34] vs 0.73 [0.31]; β coefficient, −0.02; 95% CI, −0.03 to −0.01) than men. Compared with men, women with premature ICVD were less likely to receive antiplatelet (64.5% vs 77.9%; OR, 0.76; 95% CI, 0.70-0.82), any statin (54.8% vs 72.3%; OR, 0.67; 95% CI, 0.62-0.73), or HIS therapy (20.4% vs 35.0%; OR, 0.67; 95% CI, 0.62-0.73; Table 3). Similarly, women with premature PAD were comparatively less likely to receive antiplatelet (58.9% vs 78.2%; OR, 0.62; 95% CI, 0.53-0.73), any statin (58.4% vs 74.2%; OR, 0.81; 95% CI, 0.70-0.93), and HIS therapy (25.2% vs 38.1%; OR, 0.82; 95% CI, 0.69-0.94; Table 4). Among patients with premature ICVD and PAD, there were no sex-associated differences in statin adherence.

Table 2. Aspirin Use, Statin Use, and Statin Adherence Among Patients With Premature Ischemic Heart Disease.

Variable	No. (%) with premature IHD^a		Adjusted OR (95% CI), β coefficient^a	P value
Variable	Women (n = 6332)	Men (n = 110 329)	Adjusted OR (95% CI), β coefficient^a	P value
Antiplatelet use^b	3775 (64.0)	81 012 (82.5)	0.47 (0.45 to 0.50)	<.001
Any statin use	3995 (63.1)	86 493 (78.4)	0.62 (0.59 to 0.66)	<.001
High-intensity statin use	1817 (28.7)	46 111 (41.8)	0.63 (0.59 to 0.66)	<.001
Statin PDC ≥0.8	2319 (50.4)	53 398 (56.4)	0.95 (0.89 to 1.01)	.10
Statin PDC, mean (SD)	0.68 (0.34)	0.73 (0.31)	−0.02 (−0.03 to −0.01)	<.001

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Abbreviations: ASCVD, atherosclerotic cardiovascular disease; IHD, ischemic heart disease; OR, odds ratio, PDC, proportion of days covered.

^{^a}

Adjusted for patient’s age, race/ethnicity, obesity (body mass index ≥30; calculated as weight in kilograms divided by height in meters squared), hypertension, diabetes, type of ASCVD (ischemic heart disease only vs ischemic heart disease + ischemic cardiovascular disease vs ischemic heart disease + peripheral arterial disease vs ischemic heart disease + ischemic cardiovascular disease +peripheral arterial disease), major depressive disorder, posttraumatic stress disorder, statin-associated adverse effects, Medicaid status, clinicians type (physician vs advanced practice clinicians), teaching facility (vs nonteaching facility), urban (vs rural) facility, number of cardiology visits 12 months prior to index primary care provider visit, number of primary care provider visits 12 months prior to index primary care provide visit, and diagnostic cost group relative risk score.

^{^b}

Antiplatelet use analysis included patients who were prescribed aspirin, ticagrelor, clopidogrel, prasugrel, and ticlopidine.

Table 3. Aspirin Use, Statin Use, and Statin Adherence Among Patients With Premature Ischemic Cerebrovascular Disease.

Outcome variable	No. (%) with premature ICVD		Adjusted OR (95% CI), β coefficient^a	P value
Outcome variable	Women (n = 4355)	Men (n = 35 964)	Adjusted OR (95% CI), β coefficient^a	P value
Antiplatelet use^b	2518 (64.5)	23 898 (77.9)	0.78 (0.72 to 0.84)	<.001
Any statin use	2386 (54.8)	26 012 (72.3)	0.69 (0.64 to 0.74)	<.001
High-intensity statin use	887 (20.4)	12 573 (35.0)	0.67 (0.62 to 0.73)	<.001
Statin PDC ≥0.8	1394 (50.1)	15 347 (53.1)	1.04 (0.96 to 1.12)	.38
Statin PDC, mean (SD)	0.67 (0.35)	0.70 (0.32)	−0.01 (−0.02 to 0.01)	.23

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Abbreviations: ASCVD, atherosclerotic cardiovascular disease, ICVD, ischemic cerebrovascular disease, OR, odds ratio, PDC, proportion of days covered.

^{^a}

^{^b}

Antiplatelet use analysis included patients who were prescribed aspirin, ticagrelor, clopidogrel, prasugrel, and ticlopidine.

Table 4. Aspirin Use, Statin Use, and Statin Adherence Among Patients With Premature PAD.

Outcome variable	No. (%) with premature PAD		Adjusted OR (95% CI), β coefficient^a	P value
Outcome variable	Women (n = 1022)	Men (n = 18 036)	Adjusted OR (95% CI), β coefficient^a	P value
Antiplatelet use^b	516 (58.9)	11 753 (78.2)	0.62 (0.53 to 0.73)	<.001
Any statin use	597 (58.4)	13 376 (74.2)	0.81 (0.70 to 0.93)	.003
High-intensity statin use	258 (25.2)	6867 (38.1)	0.80 (0.69 to 0.94)	.006
Statin PDC ≥0.8	346 (50.4)	7870 (53.1)	1.10 (0.94 to 1.29)	.23
Statin PDC, mean (SD)	0.68 (0.33)	0.71 (0.32)	0.01 (−0.01 to 0.04)	.28

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Abbreviations: ASCVD, atherosclerotic cardiovascular disease; OR, odds ratio; PAD, peripheral arterial disease; PDC, proportion of days covered.

^{^a}

^{^b}

Antiplatelet use analysis included patients who were prescribed aspirin, ticagrelor, clopidogrel, prasugrel, and ticlopidine.

We identified 9485 patients (1340 women and 8145 men) as having extremely premature ASCVD (eTable 3 in the Supplement). In this group, women were younger (mean [SD], 34.5 [4.72] years) than men (35.4 [4.47] years). Among women, compared with men, there was a higher proportion of African American patients (36.8% [n = 493] vs 23.2% [n = 1886]) but slightly lower proportion of White patients (55.0% [n = 737] vs 67.8% [n = 5524]) and Asian patients (1.3% [n = 17] vs 1.5% [n = 118]). Additionally, women had higher prevalence of ICVD (49.7% [n = 666] vs 28.5% [n = 2320]) and MDD and/or PTSD (57.0% [n = 764] vs 49.8% [n = 4052]) but had lower IHD prevalence (48.2% [n = 646] vs 72.0% [n = 5863]). However, there was no difference in PAD (8.2% [n = 110] vs 7.6% [n = 622]; P = .47). Women were less likely than men to be obese (BMI ≥30; 51.9% [n = 696] vs 59.7% [n = 4865]), have hypertension (69.7% [n = 934] vs 86.2% [n = 7017]), or have diabetes (21.8% [n = 292] vs 28.7% [n = 2339]). Moreover, women had comparatively lower LDL-C levels (136.3 mg/dL vs 148.6 mg/dL), and a lower proportion saw a cardiologist (18.1% [n = 243] vs 22.8% [n = 1857]).

In this extremely premature ASCVD group, women used comparatively less antiplatelets (37.7% [n = 455] vs 56.5% [n = 4165]; P < .001), statins (29.0% [n = 389] vs 52.3% [n = 4257]; P < .001), and HIS (10.4% vs 27.2%, P < .001) (eTable 4 in the Supplement). After adjusted analyses, female sex was independently associated with lower odds of aspirin (OR, 0.61; 95% CI, 0.53-0.70), any statin (OR, 0.51; 95% CI, 0.44-0.58), and HIS use (OR, 0.45; 95% CI, 0.37-0.54). However, there were no significant sex-associated differences in PDC of at least 0.8 (47.0% vs 47.2%; P = .84) or mean statin PDC (mean [SD], 0.64 [0.36] vs 0.65 [0.35]; P = .61; eTable 5 and eFigure 2 in the Supplement).

Lastly, interaction testing evaluated for the effect of Black race and female sex on the measured outcomes. Relative to women of other races, Black women were less likely to receive some therapies but also more likely to receive others. There was no heterogeneity observed regarding statin adherence. Specifically, Black women with (1) premature ASCVD were more likely to receive any statins (OR, 1.15; 95% CI, 1.05-1.26; P = .007); (2) premature IHD were more likely to receive antiplatelets (OR, 1.28; 95% CI, 1.13-1.45; P < .001); (3) premature PAD were less likely to receive HIS (OR, 0.69; 95% CI, 0.49-0.97; P = .043); and (4) extremely premature ASCVD were more likely to receive HIS (OR, 1.58; 95% CI, 1.07-2.34; P = .006). Hence, despite these interactions, there was no clear direction of association between Black race and female sex on the outcomes.

Discussion

Our study shows that women with premature and extremely premature ASCVD were significantly less likely to receive antiplatelets, any statin, or HIS therapy compared with men. Additionally, lower statin adherence was observed among women with premature IHD compared with men. These observed differences persisted after adjustments for clinical, socioeconomic, and clinician factors. Overall, both sexes received suboptimal aspirin and statin therapy and had poor statin adherence.

Results from this study reveal cardiovascular care disparities between women and men veterans with premature and extremely premature ASCVD. A 2014 study²⁹ demonstrated that veteran status alone may contribute to cardiovascular disease (CVD) risk, independent of sociodemographic, clinical, or psychological factors (relative risk, 1.483; 95% CI, 1.176-1.871). Furthermore, as the population of 1.9 million women veterans is projected to increase by at least 300 000 within 25 years, our study introduces relevant aspects to this ever-growing patient group.³⁰ Despite established benefits of secondary ASCVD prophylaxis, women receive comparatively less aggressive therapy than men.³¹ Reasons for such difference in care are multifactorial, relating to both clinician and patient factors.

Nonprescription of guideline-directed statin and HIS use in women with premature and extremely premature ASCVD is partly owing to clinician unawareness and bias. Findings from the nationwide Patient and Provider Assessment of Lipid Management registry demonstrated that among individuals with high-risk ASCVD, statin-eligible women were less likely to receive statins than men (67.0% vs 78.4%) or statins at guideline-recommended intensity (36.7% vs 45.2%). After adjustment for patient-, clinical-, and physician-related factors, the sex-dependent findings persisted. Women were less likely to receive any statin (OR, 0.70; 95% CI, 0.61-0.81) or guideline-recommended statin (OR, 0.82; 95% CI, 0.73-0.92).³² It is well-established that women with ASCVD, particularly IHD, often present with atypical symptoms.^33,34 However, underrecognition of ASCVD in women still persists today.^35,36

In a study evaluating cardiovascular care among veterans at high-risk for ASCVD,³⁷ women veterans reported higher stress levels, lower confidence, more depression, and inadequate social support than men.³⁷ Moreover, patients may resist statins owing to concerns of SAAEs.³⁸ Feared SAAEs involve teratogenicity in women of child-bearing age, increased drug-drug interactions, muscle weakness, and perceived lack of overall safety.^39,40 Concordantly, a nationwide survey assessing perception of heart disease as the leading cause of death found women were comparatively less aware in 2019 (44%) than in 2009 (65%), with most lower awareness occurring among young women aged 25 to 34 years.⁴¹

Across all patient groups, we observed suboptimal secondary prevention therapy of antiplatelets and statins. The most pronounced disparity involved HIS, with observed use in 23.5% and 10.4% of women with premature and extremely premature ASCVD, respectively. Our analyses also indicated that 38.1% of men in the premature and only 27.2% of men in the extremely premature ASCVD group received HIS. A possible reason for such substandard treatment is falsely low clinician perceptions of patients’ recurrent ASCVD risk, especially in patients with extremely premature ASCVD.^42,43 Such diagnostic inattentiveness toward young patients may result in higher thresholds to initiate or escalate care, resulting in a phenomenon called “clinical therapeutic inertia.”^44,45 Similarly, our findings show significantly lower prescription rates in the extremely premature ASCVD group. Ironically, these young patients possess the most potential “disability-adjusted life years” salvageable.^46,47 Complacency in secondary cardiovascular prophylaxis in this young cohort can result in devastating long-term consequences with poorer quality of life. This is especially true for women younger than 45 years with premature CAD, who have worse mortality outcomes compared with men.¹¹

These concerning trends in young women have spurred initiatives such as the American Heart Association’s Go Red for Women campaign and VA initiatives such as the EMPOWER trial (NCT02991534). However, efforts focused on secondary prevention of ASCVD are needed to avoid further ASCVD-related morbidity and mortality in this young population.

Limitations

Our study’s observational design and EMR constraints limited assessment of variables such as statin or aspirin contraindications, aspirin allergies and over-the-counter use, outside-VA pharmacy use, and lifestyle modifications. Although we measured Medicaid status, other socioeconomic aspects of homelessness, education, and marital status could not be captured. Facility-level care variation was possible, owing to the large database size and inclusion of women-only clinics as the “PCP visit.” However, adjustment for facility-related factors mitigated this effect. During our study period, VA records did not discern between “birth sex” and “self-identified gender identity.” Thus, we were unable to ascertain transgender status (approximately 0.1% of veterans).^48,49

Veterans Affairs’ patient sampling inevitably entails underrepresentation of women. However, our inclusion of 11 753 women veterans offers much-needed insight into this important and ever-growing population. From 2005 to 2015, women enrolled in VA health services nearly doubled to more than 720 000. Despite these rising numbers, less is understood regarding their health care needs. However, we do know that significant veteran-civilian differences extend across demographic, socioeconomic, and cardiovascular risks.⁵⁰ The 2017 Veterans Report showed that compared with civilians, more women veterans are Black (12% vs 20%-30%), similar to our cohort (approximately 30%).^30,51 Notably, Black individuals had higher ICVD risk (relative risk, 5.85; 95% CI, 1.82-18.73) than White individuals.⁵² Compared with nonveterans, more women veterans had divorced (23.4% vs 12.6%), had a college education (44% vs 32%), or had more than 1 insurance (30% vs 13.9%). Women veterans were less likely than nonveterans to be in poverty (10% vs 15%) or uninsured (4% vs 9%). However, women veterans reported less social support than nonveterans, evident by lower social diversity scores and smaller social networks.^51,53 In a VA study evaluating sex differences in cardiovascular health, age-adjusted analyses showed women aged 18 to 44 years had comparable cardiometabolic factors as nonveterans but had more depression.⁵⁴ Likewise, a large VA employee health study demonstrated similar rates of physical activity, diabetes, and hypertension between women veterans and civilians. However, women veterans reported more depression, PTSD, sleep disorders, and tobacco use.⁵⁵ Henceforth, compared with nonveterans, women veterans likely represent a high-risk group.⁵⁰ Our results highlight the need for better medical management of ASCVD in this high-risk group of women veterans, who represent a sizeable population.

Conclusions

To our knowledge, this is the first study to evaluate nationwide sex-based cardiovascular care disparities in premature and extremely premature ASCVD patients. In the past 20 years, women’s cardiovascular health has garnered more national attention. However, despite this increased coverage, gaps in women’s cardiovascular health care delivery still persist, particularly for women veterans. Findings from our study show that sex-based heterogeneity in secondary prevention affects women with premature and extremely premature ASCVD. Moreover, ASCVD extension into the child-bearing age group was previously unknown. Awareness of this phenomenon will be critical in curbing ASCVD-associated financial and health costs for affected women.

A systems-based approach toward improvement of sex-based health care delivery necessitates prompt efforts to narrow sex-based health care delivery gap for women. From the clinician’s standpoint, increasing awareness and incorporating a tailored discussion regarding secondary prevention therapies for women of child-bearing age should be emphasized. As exact reasons for sex-based heterogeneity in premature and extremely premature ASCVD remain unclear, further investigation and outcomes research are needed to elucidate potential causes and effective solutions. First, qualitative surveys of clinicians and patients will better assess potential drivers of this disparity. After identifying gaps in current health care, addressing those issues will require implementing system-level interventions to improve guideline-concordant practices among clinicians and medication adherence among patients.

Supplement.

eFigure 1. Cross-sectional analysis of antiplatelet and high-intensity statin use among patients with premature and extremely premature ASCVD

eFigure 2. Antiplatelet therapy, statin use, and statin adherence among patients with extremely premature ASCVD

eTable 1. ASCVD Subtype Identification Criteria by Diagnostic and Procedural Codes

eTable 2. Aspirin use, statin use, and statin adherence among patients with premature ASCVD

eTable 3. ASCVD Subtype Characterization and Prevalence

eTable 4. Baseline Characteristics of patients with extremely premature ASCVD

eTable 5. Aspirin use, statin use, and statin adherence among patients with extremely premature ASCVD

Click here for additional data file.^{(392.9KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eFigure 1. Cross-sectional analysis of antiplatelet and high-intensity statin use among patients with premature and extremely premature ASCVD

eFigure 2. Antiplatelet therapy, statin use, and statin adherence among patients with extremely premature ASCVD

eTable 1. ASCVD Subtype Identification Criteria by Diagnostic and Procedural Codes

eTable 2. Aspirin use, statin use, and statin adherence among patients with premature ASCVD

eTable 3. ASCVD Subtype Characterization and Prevalence

eTable 4. Baseline Characteristics of patients with extremely premature ASCVD

eTable 5. Aspirin use, statin use, and statin adherence among patients with extremely premature ASCVD

Click here for additional data file.^{(392.9KB, pdf)}

[hoi210018r1] 1.GBD 2016 Causes of Death Collaborators . Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1151-1210. doi: 10.1016/S0140-6736(17)32152-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Sex-Related Disparities in Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease

Michelle T Lee, MD, PharmD

Dhruv Mahtta, DO, MBA

David J Ramsey, PhD

Jing Liu, MD

Arunima Misra, MD

Khurram Nasir, MD, MPH

Zainab Samad, MBBS, MHS

Dipti Itchhaporia, MD

Safi U Khan

Richard S Schofield, MD

Christie M Ballantyne, MD

Laura A Petersen, MD, MPH

Salim S Virani, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Results

Table 1. Baseline Characteristics of Patients With Premature Atherosclerotic Cardiovascular Disease.

Figure. Antiplatelet Therapy, Statin Use, and Statin Adherence Among Patients With Premature Atherosclerotic Cardiovascular Disease (ASCVD).

Table 2. Aspirin Use, Statin Use, and Statin Adherence Among Patients With Premature Ischemic Heart Disease.

Table 3. Aspirin Use, Statin Use, and Statin Adherence Among Patients With Premature Ischemic Cerebrovascular Disease.

Table 4. Aspirin Use, Statin Use, and Statin Adherence Among Patients With Premature PAD.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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