Females are Less Likely to Receive Best Medical Therapy for Stroke Prevention Before and After Carotid Revascularization than Males

Abstract

Background:

Current professional guidelines recommend best medical therapy (BMT) with statin agents and antiplatelet therapy for primary and secondary stroke prevention in patients with carotid artery stenosis. We aimed to assess the association of patient sex with preoperative BMT in patients undergoing carotid revascularization.

Methods:

We performed a retrospective review of Vascular Quality Initiative (VQI) patients who underwent carotid endarterectomy or carotid artery stenting between January 2003 and February 2022. Multivariable logistic regression models were used to assess the association of patient sex with preoperative BMT after adjusting for sociodemographic, comorbidity, and disease severity characteristics. In-hospital outcomes were assessed by sex and preoperative BMT status.

Results:

Of 214,008 patients who underwent carotid revascularization, 38.7% (n=82,855) were female and 61.3% (n=131,153) were male. Overall, 77.2% (n=63,922) of females were on preoperative BMT, compared to 80.4% (n=105,375) of males (P<0.001). After adjusting for baseline differences, females had 11% lower odds of being on BMT compared to males (adjusted OR 0.89, 95% CI 0.86, 0.91). Postoperatively, females had 18% lower odds of being prescribed BMT than males (aOR 0.82, 95% CI 0.79, 0.84). In-hospital stroke (1.20% vs. 1.51%), death (0.37% vs. 0.66%), and stroke/death (1.46% vs. 1.98%) were all significantly lower for patients on BMT (all, P<0.001).

Conclusions:

There is a significant discrepancy in the proportion of females versus males receiving preoperative BMT for stroke prevention prior to carotid artery revascularization. In-hospital outcomes are worse in patients without BMT, highlighting the importance of raising awareness and implementing targeted interventions to improve preoperative adherence to stroke prevention guidelines.

Table of Contents Summary

In this retrospective review of 214,008 patients with carotid artery stenosis, females were less likely to be on preoperative best medical therapy for stroke prevention compared to their male counterparts when presenting for carotid artery revascularization. Our findings reveal a discrepancy in adherence to stroke prevention guidelines for females versus males.

Introduction

Current American Heart Association (AHA)/American Stroke Association (ASA) guidelines recommend best medical therapy (BMT) with statin agents and antiplatelet therapy for secondary stroke prevention in patients with a history of ischemic stroke or transient ischemic attack (TIA)¹. In certain high-risk individuals, including all patients with carotid artery stenosis, BMT is also recommended for primary stroke prevention¹. The Society for Vascular Surgery’s (SVS) carotid guidelines also recommend BMT for secondary stroke prevention and for primary prevention of cardiovascular morbidity in patients with carotid stenosis of any grade^{2, 3}.

Meta-analyses have shown that the prescription prevalence of aspirin for women at high risk for cardiovascular disease is significantly lower than that for men in the general (non-surgical) population⁴. The same has been shown of the prescription prevalence of statins in high-risk women relative to men⁵. A retrospective analysis of 151 patients with symptomatic carotid artery stenosis at a single institution between 2012 and 2019 also demonstrated that significantly fewer females were on preoperative aspirin and statin therapy than their male counterparts when presenting for carotid artery revascularization (Bose et al., Thirty-fourth Annual Meeting of the Eastern Vascular Society, 2020). However, the prevalence of BMT in patients with carotid artery stenosis undergoing revascularization has not been well described on a national scale.

In this study, we aimed to assess the association of patient sex with BMT in patients undergoing carotid revascularization in the United States. We hypothesize that discrepancies in BMT will exist between females and males presenting for carotid revascularization, with females being less likely to receive BMT for stroke prevention relative to their male counterparts.

Methods

Study Population

We included all patients who underwent carotid revascularization between January 2003 and February 2022 in the SVS Vascular Quality Initiative (VQI). Patients who were missing information on sex (n=5), age (n=1), symptomatic status (n=2,965), or documentation of preoperative aspirin, P2Y inhibitor, or statin usage (n=318) were excluded. Patients who were less than 18 years old (n=255), American Association of Anesthesiologists (ASA) class V (n=241), underwent intracranial stenting (n=1,195), any carotid stenting procedure that was not transfemoral carotid artery stenting (TFCAS) or transcarotid artery stenting (TCAR) (n=5,998), or were reported to have <50% carotid artery stenosis (n=6,368) or 100% occlusion (n=3,096) on the side of surgery were also excluded. This study design was established in consideration of STROBE guidelines⁶. Study approval was obtained from the Johns Hopkins Medicine Institutional Review Board and the VQI Arterial National Research Advisory Committee.

Definitions

The main exposure of the study was patient sex (as assigned at birth), as reported in the VQI database. The primary outcome of the study was preoperative BMT use, which was defined as being on both an antiplatelet agent (aspirin or P2Y inhibitor) and a statin preoperatively. Secondary outcomes included in-hospital stroke, death, composite stroke/death, and myocardial infarction (MI), as defined by the VQI⁷.

Other covariates included patient sociodemographic factors (age, race/ethnicity, primary insurance payor, area deprivation index [ADI]), ASA class, functional status, admission location, comorbidities (smoking, hypertension, diabetes, chronic obstructive pulmonary disease [COPD], chronic kidney disease [CKD], cardiac history), preoperative medication use, degree of carotid artery stenosis, operative approach, and operative urgency. Age was divided into two group (<70 years vs ≥70 years) based on mean age of the cohort, different perioperative outcomes in older patients⁸, and some antiplatelet prescribing hesitancy for patients above age 70¹. ADI is a validated composite metric of geographic socioeconomic disadvantage that incorporates household income, education, employment, and housing quality⁹. CKD was defined as a glomerular filtration rate of less than 60 mg/mmol calculated using creatinine clearance (μmol/L),¹⁰ functioning kidney transplant, and/or dialysis. High-grade carotid artery stenosis was defined as either an ICA/CCA ratio ≥4 on duplex ultrasonography or ≥70% stenosis on pre-operative magnetic resonance angiography, computed tomography angiography, angiogram, or other imaging. Symptomatic status was defined as a documented history of ipsilateral TIA, stroke, or neurologic event, as defined in the VQI⁷. Operative approach was classified as carotid endarterectomy (CEA), TFCAS, and TCAR. All other definitions were determined using the standard VQI reporting definitions⁷.

Statistical Analysis

Student’s t-tests and Chi-square statistics were used to evaluate differences between females and males undergoing carotid revascularization. Multivariable logistic regression was used to assess the association of patient sex with preoperative BMT. All covariates with P<0.05 were included in the initial model, and then Akaike information criterion was used to select the best fit regression model. Procedure type was removed from the final adjusted model due to perfect collinearity of TCAR with BMT. Univariable and multivariable logistic regression models were also used to assess the association of patient sex with BMT prescribed on discharge (i.e., postoperative BMT).

We performed a sensitivity analysis where BMT was redefined as either the use of anticoagulation with a statin or the use of an antiplatelet agent with a statin, based on the finding that antiplatelet and statin use was significantly lower among patients on anticoagulation therapy. We also performed a series of subgroup analyses assessing the relationship of patient sex with BMT based on symptomatic status, coronary revascularization history, and any cardiac history (including symptomatic or asymptomatic angina, MI, or coronary revascularization) after full adjustment. Annual temporal trends in preoperative BMT were stratified by patient sex and compared using Chi-square analyses. A linear regression model was used to assess the change in preoperative BMT use over the study period. Finally, we assessed the association of BMT with in-hospital outcomes using univariable analyses, overall and stratified by patient sex and BMT status.

All statistical analyses were performed using Stata/SE 17 (College Station, TX, USA) with statistical significance set at P<0.05. Additional image creation was performed using GraphPad Prism v. 9.2.0 (GraphPad Software, San Diego, CA).

Results

Best Medical Therapy in Females versus Males

Of 214,008 patients who were included in the analysis, 38.7% (n=82,855) were female and 61.3% (n=131,153) were male. Overall, 79.1% of patients were on preoperative BMT, including 77.2% (n=63,922) of females and 80.4% (n=105,375) of males (P<0.001). When BMT was analyzed according to antiplatelet agent, fewer females were on both aspirin with a statin (71.4% vs 75.2%; P<0.001) and P2Y inhibitor with a statin (42.3% vs 45.5%; P<0.001). Stratifying by procedure type, a larger proportion of patients were on BMT before undergoing TCAR than any other procedure, with 86.4% of females (n=7,786) and 89.2% of males (n=13,644) on preoperative BMT. This is compared to the 78.2% (n=9,072) of females and 80.2% (n=16,392) of males on BMT who underwent TFCAS, and 75.6% (n=46,978) of females and 79.0% (n=75,231) of males who underwent a CEA (Figure 1).

Figure 1.

Proportion of patients on best medial therapy (BMT), stratified by patient sex and procedure type, including carotid endarterectomy (CEA), transfemoral carotid artery stenting (TFCAS), and transcarotid artery revascularization (TCAR).

Other notable differences (≥3%) between females and males included a higher prevalence of current smoking, COPD, and CKD among females; and a higher prevalence of independent ambulatory status, cardiac disease, and use of anticoagulation among males (all, P<0.001; Table 1). A complete list of patient baseline characteristics is provided in Table 1.

Table 1.

Sociodemographic, comorbidity, and disease severity characteristics of patients undergoing carotid revascularization, stratified by sex (Vascular Quality Initiative, 2003–2022)

	Females (N= 82,855, 38.7%)	Males (N= 131,153, 61.3%)	P-value
Age, years (mean ± SD)	70.7 ± 9.5	71.0 ± 9.1	<0.001
<70 years	36,534 (43.0)	57,230 (42.4)	0.01
>70 years	48,516 (57.0)	77,726 (57.6)
Ethnicity/Race			<0.001
Non-Hispanic White	72,411 (87.7)	116,833 (89.4)
Non-Hispanic Black	5,130 (6.2)	4,903 (3.7)
Hispanic	2,537 (3.1)	4,520 (3.5)
Other	2,467 (3.0)	4,412 (3.4)
Primary Insurer			<0.001
Public Payor (Medicare, Medicaid, VA)	50,884 (66.9)	79,312 (65.6)
Commercial	24,164 (31.7)	39,891 (33.0)
Other	1,052 (1.4)	1,669 (1.4)
Admission from Home (vs Nursing Home/Homeless)	81,499 (98.5)	129,379 (98.8)	<0.001
Independently Ambulatory	52,561 (87.1)	84,707 (90.3)	<0.001
ASA Class			<0.001
I / II	5,475 (6.9)	8,759 (6.9)
III	58,260 (73.0)	89,761 (71.0)
IV	16,029 (20.1)	27,859 (22.0)
Area Deprivation Index			<0.001
ADI-1(least deprived)	10,386 (12.6)	19,270 (14.8)
ADI-2	25,414 (30.9)	41,492 (31.9)
ADI-3	30,951 (37.6)	47,463 (36.5)
ADI-4 (most deprived)	15,471 (18.8)	21,882 (16.8)
Smoking			<0.001
Never	23,971 (29.0)	30,635 (23.4)
Prior	35,113 (42.4)	68,555 (52.3)
Current	23,699 (28.6)	31,861 (24.3)
Hypertension	74,436 (89.8)	117,396 (89.5)	0.02
Diabetes			<0.001
Diet/Medication-Controlled Diabetes	18,928 (22.9)	31,149 (23.8)
Insulin-Dependent Diabetes	11,469 (13.9)	16,803 (12.8)
Treated COPD	16,673 (20.1)	19,207 (14.7)	<0.001
Chronic Kidney Disease	29,709 (36.2)	33,134 (25.5)	<0.001
Any Cardiac History	33,070 (42.1)	67,322 (53.5)	<0.001
Symptomatic CAD/History of MI	22,531 (27.3)	46,712 (35.7)	<0.001
Prior CABG/PCI	22,339 (28.8)	52,280 (42.1)	<0.001
Congestive Heart Failure	9,982 (12.1)	17,037 (13.0)	<0.001
Best Medical Therapy	63,922 (77.2)	105,375 (80.4)	<0.001
BMT including Anticoagulation+Statin	64,991 (78.9)	107,356 (82.3)	<0.001
Aspirin + Statin	59,185 (71.4)	98,573 (75.2)	<0.001
P2Y Inhibitor + Statin	34,165 (42.3)	58,288 (45.5)	<0.001
Anticoagulation + Statin	6,228 (8.0)	13,658 (11.1)	<0.001
Aspirin	69,520 (83.9)	112,568 (85.8)	<0.001
Statin	68,368 (82.5)	111,727 (85.1)	<0.001
P2Y Inhibitor	39,290 (47.4)	65,157 (49.7)	<0.001
Beta-Blocker	45,337 (52.7)	74,381 (54.4)	<0.001
ACE Inhibitor	39,640 (52.0)	64,347 (53.2)	<0.001
Anticoagulation	7,411 (9.7)	15,654 (13.0)	<0.001
Symptomatic Disease	39,414 (47.6)	65,359 (49.9)	<0.001
Degree of Stenosis			0.20
Moderate-Grade (<70%)	78,025 (10.0)	12,864 (10.1)
High-Grade (≥70%)	69,595 (90.0)	109,084 (89.8)
Type of Procedure			<0.001
CEA	62,147 (75.1)	95,289 (72.7)
TF-CAS	11,598 (14.0)	20,435 (15.6)
TCAR	9,011 (10.9)	15,300 (11.7)
Urgency of Operation			<0.001
Elective	71,822 (86.8)	111,975 (85.5)
Urgent/Emergent	10,945 (13.2)	19,037 (14.5)

Note: SD is standard deviation. VA is Veterans Affairs. ASA is the American Society of Anesthesiologists. COPD is chronic obstructive pulmonary disease. CAD is coronary artery disease. MI is myocardial infarction. CABG is coronary artery bypass graft. PCI is percutaneous coronary intervention. CEA is carotid endarterectomy. TF-CAS is transfemoral carotid artery stenting. TCAR is transcarotid artery revascularization.

Association of Patient Characteristics with Best Medical Therapy

After adjusting for sociodemographic factors, comorbidities, and disease severity, female sex was associated with lower odds of preoperative BMT than male sex (adjusted OR [aOR] 0.89, 95% CI 0.86, 0.91). Other patient factors associated with lower odds of preoperative BMT included older age, increasing ADI (i.e., more socioeconomic deprivation), CKD, and anticoagulant use (all, P<0.001; Table 2). Factors associated with higher odds of BMT included commercial (vs. public) insurance, former (vs. never) smoking, hypertension, diabetes, history of coronary artery revascularization, symptomatic carotid artery stenosis, beta-blocker use, and angiotensin-converting enzyme (ACE) inhibitor use (all, P<0.001; Table 2).

Table 2.

Logistic regression models (OR, 95% CI) assessing the association of patient sex and other covariates with preoperative best medical therapy prior to carotid artery revascularization

Covariate	Unadjusted OR (95% CI)	Adjusted aOR (95% CI)
Female Sex	0.83 (0.81, 0.84)	0.89 (0.86, 0.91)
Age ≥70 years	0.92 (0.90, 0.94)	0.86 (0.84, 0.89)
Race/Ethnicity	–	–
Non-Hispanic White	Ref	Ref
Non-Hispanic Black	1.05 (1.00, 1.10)	1.06 (0.99, 1.13)
Hispanic	1.11 (1.05, 1.18)	1.04 (0.97, 1.12)
Other	1.17 (1.10, 1.24)	1.04 (0.96, 1.13)
Payor
Public Payor (Medicare, Medicaid, VA)	Ref	Ref
Commercial	1.03 (1.01, 1.05)	1.06 (1.03, 1.09)
Other	0.91 (0.83, 1.00)	1.04 (0.93, 1.17)
Admission from Home (vs. Nursing Home/Homeless)	0.97 (0.89, 1.05)	0.96 (0.86, 1.07)
Independent Ambulation	0.98 (0.95, 1.01)	0.98 (0.94, 1.02)
ASA Class
I / II	Ref	Ref
III	1.16 (1.11, 1.20)	1.06 (1.01, 1.13)
IV	1.12 (1.07, 1.18)	0.98 (0.92, 1.04)
Area Deprivation Index
ADI-1 (Least Deprived)	Ref	Ref
ADI-2	0.96 (0.92, 0.99)	0.95 (0.91, 0.99)
ADI-3	0.87 (0.84, 0.90)	0.83 (0.80, 0.87)
ADI-4 (Most Deprived)	0.83 (0.78, 0.86)	0.77 (0.73, 0.80)
Smoking		–
Never	Ref	Ref
Former	1.19 (1.16, 1.22)	1.13 (1.10, 1.17)
Current	1.01 (0.98, 1.04)	1.00 (0.97, 1.05)
Hypertension	1.59 (1.54, 1.65)	1.13 (1.08, 1.17)
Diabetes
No Diabetes	Ref	Ref
Medicated Diabetes	1.30 (1.26, 1.32)	1.15 (1.11, 1.18)
Insulin-dependent Diabetes	1.38 (1.33, 1.42)	1.20 (1.15, 1.25)
Treated COPD	1.02 (0.99, 1.05)	1.00 (0.96, 1.04)
Chronic Kidney Disease	0.97 (0.95, 1.00)	0.90 (0.88, 0.93)
Cardiac History	1.49 (1.46, 1.52)	—
Symptomatic CAD/History of MI	1.59 (1.55, 1.63)	—
Prior CABG/PCI	1.61 (1.58, 1.65)	1.58 (1.53, 1.63)
Congestive Heart Failure	1.15 (1.11, 1.19)	0.94 (0.90, 0.99)
Beta-blocker	1.46 (1.42, 1.49)	1.35 (1.32, 1.39)
ACE Inhibitor	1.48 (1.44, 1.51)	1.34 (1.30, 1.37)
Anticoagulation	0.64 (0.62, 0.66)	0.52 (0.50, 0.54)
Symptomatic Disease	1.12 (1.10, 1.15)	1.30 (1.26, 1.33)
High-Grade (≥70%) Stenosis	0.92 (0.89, 0.96)	0.97 (0.93, 1.01)
Type of Procedure
CEA	Ref	–
TCAR	1.12 (1.08, 1.15)	–
TF-CAS	2.14 (2.06, 2.23)	–

Notes: Akaike information criterion was used to select the best fit model.

SD is standard deviation. VA is Veterans Affairs. ASA is the American Society of Anesthesiologists. COPD is chronic obstructive pulmonary disease. CAD is coronary artery disease. MI is myocardial infarction. CABG is coronary artery bypass graft. PCI is percutaneous coronary intervention. ACE is angiotensin-converting enzyme. CEA is carotid endarterectomy. TF-CAS is transfemoral carotid artery stenting. TCAR is transcarotid artery revascularization.

Sensitivity Analyses

In a sensitivity analysis where BMT was redefined as either anticoagulation with a statin or antiplatelet agent (aspirin or P2Y inhibitor) with a statin, the odds of being on preoperative BMT were persistently lower in females compared to males (78.9% vs. 82.3%; P<0.001). After adjusting for baseline differences between groups, female sex was persistently associated with lower odds of BMT relative to male sex (aOR 0.88, 95% CI 0.86, 0.91; Supplemental Table 1).

Female sex was also persistently associated with lower odds of BMT relative to male sex in subgroup analyses limited to patients with symptomatic carotid disease, asymptomatic carotid disease, history of coronary revascularization, and history of any cardiac disease (Figure 2).

Figure 2.

Forest plot depicting subgroup analyses assessing the association of female sex with best medical therapy (BMT) for patients according to symptom status, coronary revascularization history, and any cardiac history

Footnote: Adjusted odds ratios are based on multivariable logistic regression models adjusted for sex, age, race/ethnicity, payor, area deprivation index, smoking status, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, admission location, ambulatory status, ASA class, beta-blocker use, angiotensin-converting enzyme inhibitor use, and anticoagulation use. Symptomatic and asymptomatic cohorts are also adjusted for coronary revascularization history. Coronary revascularization and any cardiac history cohorts are also adjusted for symptom status.

BMT Prevalence Over Time

The proportion of females and males using preoperative BMT significantly increased over the course of the study period for both groups (P < .001), starting at 50.6% for females and 56.2% for males in 2003 and increasing to 81.4% for females and 85.2% in males in 2022. Expressed annually, the proportional use of BMT increased by 1.31% (95% CI, 0.97–1.66) per year for females and by 1.30% (95% CI, 0.99–1.61) per year for males (both, P < .001). Females were consistently on BMT 3.4% less frequently than males across all study years (Figure 3).

Figure 3.

Proportion of females and males on best medical therapy (BMT) by year

Discharge BMT in Females versus Males

Of the 211,810 patients with discharge medications documented, 86.8% (84.9%, n=69,613 of females and 88.0%, n=114,256 of males) were prescribed BMT at the time of discharge. After adjusting for sociodemographic factors, comorbidities, and disease severity, female sex was associated with 18% lower odds of being prescribed postoperative BMT than male sex (aOR 0.82, 95% CI 0.79, 0.84).

In-Hospital Outcomes

Frequency of in-hospital stroke, death, and stroke/death were similar for females versus males (all, P>0.05), but frequency of MI was higher in females (0.78% vs. 0.62%, P<0.001; Figure 4). Frequency of in-hospital stroke (1.20% vs. 1.51%), death (0.37% vs. 0.66%), and stroke/death (1.46% vs. 1.98%) were all significantly lower for patients on BMT compared to patients not on BMT (all, P<0.001).

Figure 4.

In-hospital stroke, death, stroke/death, and myocardial infarction (MI) in patients undergoing carotid revascularization, overall and stratified by sex and best medical therapy (BMT) status

Discussion

Current professional guidelines recommend BMT with statin agents and antiplatelet therapy for primary and secondary stroke prevention in patients with carotid artery stenosis^{1, 11}. Adherence to these guidelines for patients with known carotid artery stenosis has not been reported on a national scale to our knowledge, but a small single-institution study found a significant difference in BMT use between females and males undergoing symptomatic carotid revascularization (Bose et al., Thirty-fourth Annual Meeting of the Eastern Vascular Society, 2020). Thus, we aimed to assess the association of patient sex with preoperative BMT in a national cohort of patients undergoing carotid artery revascularization. We found that 22.9% of females and 19.7% of males were not on BMT, revealing a need for improvement for all patients. More concerningly, we found that females have significantly lower odds of being on preoperative BMT for stroke prevention than their male counterparts. This discrepancy persisted after risk adjustment, regardless of symptom status or cardiovascular disease history. Importantly, our study demonstrated a significantly higher stroke, death, and composite stroke/death rate within 30-days post-revascularization in patients not on BMT.

The discrepancy in BMT for females versus males is not aligned with any existing or previous stroke guidelines. In the past two decades, the AHA/ASA has never recommended prescribing different medications for stroke prevention for females and males^{1, 12, 13}. In 2005, the Women’s Health Study, a large randomized controlled trial, showed that low-dose aspirin significantly reduced the risk of ischemic stroke in women without increasing the risk of hemorrhagic stroke, a finding that has not been shown in men¹⁴. Despite this evidence that medical management is efficacious for stroke prevention for specifically women, antiplatelet and statin use has consistently been reported to be lower in women compared to men worldwide⁴. In 2014, the AHA/ASA guidelines acknowledged the findings from the Women’s Health Study, but emphasized that management recommendations for women with carotid artery disease should remain the same as the recommendations for men until further studies were completed¹⁵. In line with this, the SVS carotid guidelines have historically never mentioned patient sex^{2, 3, 11}. As such, professional guidelines have never formally advised differing BMT prescription by sex for stroke prevention.

We found that patients with a history of coronary revascularization were significantly more likely to be prescribed BMT than patients without a history of coronary revascularization. This is consistent with other studies of peripheral artery disease, which have found that patients with concomitant coronary artery disease were more likely to be on BMT than those without¹⁶. While there was a higher number of males with a history of coronary revascularization than females in our cohort, this did not account for the sex-based discrepancy in preoperative BMT observed. Our sensitivity analysis assessing the association of sex with BMT in a population limited to patients with a history of coronary revascularization or any cardiac disease revealed that females had even lower odds of being on preoperative BMT than females in the full cohort. These findings are incongruent with professional cardiac guidelines for secondary cardiovascular disease prevention¹⁷, but consistent with other studies that found a persistent gender discrepancy in the medical management of women with acute coronary syndrome relative to men¹⁸.

Patients with symptomatic carotid artery disease had greater odds of being on BMT than their asymptomatic counterparts. This suggests that BMT may be initiated for secondary stroke prevention more often than for primary stroke prevention. This is incongruent with both the AHA/ASA and SVS guidelines, which recommend that all patients with moderate- or high-grade carotid artery disease, regardless of symptom status, be on some form of BMT^{1, 11}. We also found that female patients were on preoperative BMT less often than male patients regardless of symptom status, meaning sex-based differences in preoperative medical management are present for both primary and secondary stroke prevention strategies.

Our study demonstrated social determinants of health in the management of carotid artery stenosis. Patients living in the most socioeconomically deprived neighborhoods (ADI-4) were found to have the lowest odds of being on BMT of any patient characteristic assessed. In contrast, patients on beta-blockers, ACE inhibitors, and on medications for diabetes all had higher odds of being on preoperative BMT. Taken together, these data raise substantial concern that certain populations are undertreated due to a lack of access to the healthcare system – a gap in care also mentioned in the most recent AHA/ASA guidelines¹. Consistent with this notion, patients able to afford commercial insurance had 6% greater odds of being on BMT than patients insured by a public payor.

Unfortunately, even patients who reach the healthcare system to undergo carotid revascularization are being discharged without appropriate BMT. Although the overall proportion of patients on BMT improved, from 79.1% preoperatively to 86.8% postoperatively, the gap between females and males persists, with females having 18% lower odds of receiving BMT than males. The suboptimal adherence to guideline-based medical therapy following carotid revascularization has been previously reported in a study using the Carotid Artery Revascularization and Endarterectomy registry¹⁹, but this is the first report of which we know to also emphasize sex-based disparities in postoperative BMT prescribing. While the etiology of this disparity cannot be ascertained using retrospective data, there is some evidence based on medication prescriptions in primary care that a lower incidence of cardiovascular disease at younger ages, lower health consciousness and utilization of healthcare services, less belief than men in the safety and effectiveness of cardiovascular medications, and greater risk of adverse drug reactions lead to more drug discontinuation and worse adherence in females relative to males⁴. However, the persistent under-prescribing of BMT in females more than males – even at the time of discharge following carotid revascularization – suggests other systemic factors play a role as well. There is a critical need to address substandard prescribing patterns surrounding postoperative BMT overall, and particularly in females.

Because there have been several guideline revisions as well as major advancements in medical therapy over our two-decade study period, we assessed temporal trends in preoperative BMT prevalence. While the prescription of a statin with an antiplatelet agent is well accepted today, these medications were not always widely available. The first generic statin was only introduced in the US in 2002, the same year that the AHA/ASA released stroke guidelines recommending a statin in patients with hyperlipidemia¹³. Although our study period began in 2003, widespread statin use was not immediate. Regarding aspirin, professional guidelines largely focused on the risk of cardiac disease rather than the risk of stroke in earlier years; in 2002, the AHA/ASA recommended the use of aspirin in patients with ≥10% atherosclerotic cardiovascular disease risk to improve the “balance of coronary risk reduction over bleeding and hemorrhagic stroke”¹³. It was not until the Women’s Health Study was published in 2005 that a true reduction in ischemic stroke risk was seen with low-dose aspirin¹⁴. Meanwhile, P2Y inhibitors, an antiplatelet therapy included in our definition of BMT, were first popularized with the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial in 1996, which showed that clopidogrel was more effective than aspirin in reducing composite risk of ischemic stroke, MI, or vascular-related death²⁰. However, the generic version of clopidogrel was not approved by the US Food and Drug Administration until 2012²¹, so did not become widely used until after this time. These major changes in medication availability could contribute to the increasing trend in BMT use over time. Overall, the observed trend is encouraging. However, the disparity between sexes has remained consistent through the duration of the study period, and 18.6% of females and 14.8% of males undergoing carotid revascularization were not on BMT prior to surgery as recently as 2022, suggesting there is still substantial room for improvement. The difference in preoperative BMT use was just over 3% for females compared to males. While this number seems low on an absolute scale, it has important clinical implications. Based on current US census estimates²², approximately 5 million women have carotid disease in the US²³. This translates to approximately 150,000 women being undertreated for stroke prevention compared to men. Furthermore, we demonstrated that a lack of BMT was associated with a significantly higher rate of in-hospital stroke, death, and stroke/death following carotid revascularization. These findings are consistent with others that have shown that preoperative statins^24–31 and antiplatelet therapy^31–33 reduce the risk of adverse perioperative outcomes in patients undergoing noncardiac surgery. Females have also been shown to have worse outcomes following carotid revascularization compared to males^{34, 35}, further highlighting the critical need for females to receive the risk-reducing preoperative BMT recommended for all patients¹.

This study has some important limitations. There are limitations to the VQI database itself, which is sourced from voluntarily participating institutions, and may not be representative of patients treated at non-participating hospitals in the US. The available variables also limited us to evaluating associations with patient sex assigned at birth, rather than considering the patient’s gender identity. Additionally, the aim of our study was to assess physician-reported BMT use, and we were unable to account for true patient adherence to medications prescribed. We also could not assess other recommendations in the stroke prevention guidelines that are patient-dependent, such as lifestyle factors. Furthermore, we were unable to determine the reasons that patients were not on BMT, as these details are unavailable in the dataset. Finally, there may be some residual confounding in our study that we could not account for, even with extensive risk adjustment. Despite these limitations, our data show a significant discrepancy in BMT use for females with carotid disease compared to males.

Conclusion

In a national population of patients with known carotid disease in the US, we identified a significant discrepancy in the proportion of females versus males receiving preoperative BMT at the time of carotid artery revascularization. After adjusting for baseline characteristics, females had significantly lower odds of being on BMT than their male counterparts, preoperatively and postoperatively. This discrepancy persisted in all subgroups assessed, including symptomatic and asymptomatic patients and those with a history of coronary revascularization or other known cardiac disease. Perioperative outcomes are worse in patients without BMT, highlighting the importance of raising awareness of this discrepancy and implementing targeted interventions to improve preoperative and postoperative adherence to stroke prevention guidelines.

ARTICLE HIGHLIGHTS.

Type of Research:

Retrospective review of prospectively collected Vascular Quality Initiative (VQI) data from 2003 to 2022.

Key Findings:

Among 214,008 patients who underwent carotid revascularization, significantly fewer females were on best medical therapy (BMT) for stroke prevention compared to males. After adjusting for baseline characteristics, females had persistently lower odds of being on BMT than their male counterparts. This discrepancy has persisted for two decades and was found in all sub-cohorts assessed, including symptomatic patients, asymptomatic patients, and those with known cardiovascular disease. In-hospital stroke, death, and composite stroke/death were all significantly lower for patients on BMT than those who were not.

Take Home Message:

Females have significantly lower odds of being on preoperative BMT for stroke prevention than males when presenting for carotid artery revascularization. Because perioperative outcomes are worse in patients without BMT, it is imperative that targeted interventions are implemented to improve adherence to stroke prevention guidelines.