Sex does not have an impact on perioperative transfemoral carotid artery stenting outcomes among octogenarians

Abstract

Objective:

Transfemoral carotid artery stenting (CAS) has been validated as an acceptable alternative to carotid endarterectomy in patients at high risk for open surgery. There are variable sex- and age-based differences in transfemoral CAS outcomes of published randomized controlled trials. The aim of our study was to evaluate sex-based differences in perioperative outcomes after transfemoral CAS performed in octogenarians.

Methods:

The National Surgical Quality Improvement Program targeted vascular module was queried for all patients ≥80 years of age who underwent transfemoral CAS between 2011 and 2017. Symptomatic status was defined as a history of prior ipsilateral stroke, transient ischemic attack, or amaurosis fugax. The primary outcome was a composite outcome of perioperative (30-day) stroke or death. Outcomes were compared for male vs female patients and stratified by symptomatic status using univariate and multivariable logistic regression analyses adjusting for emergent status, symptomatic status, comorbidities, and use of an embolic protection device.

Results:

Overall, there were 143 patients ≥80 years of age who underwent transfemoral CAS during the study period, including 95 men (66.4%) and 48 women (33.6%). Race (white, 88.0% vs 85.4%), symptomatic status (30.9% vs 29.2%), and degree of stenosis (severe, 71.6% vs 62.5%) were not significantly different for men vs women (P ≥ .27). Periprocedural stroke/death occurred in six men (6.4%) vs two women (4.2%; P = .59) and did not significantly differ when stratified according to symptomatic (6.9% vs 7.1%; P = .98) and asymptomatic (6.2% vs 2.9%; P = .49) status. Based on multivariable analysis, independent factors associated with the composite end point included emergent vs elective status (adjusted odds ratio OR [aOR], 20.3; 95% confidence interval [CI], 2.25–183) and failure to use an embolic protection device (aOR, 2.86; 95% CI, 1.59–50.0). Sex was not significantly associated with the primary outcome after risk adjustment (aOR, 0.81; 95% CI, 0.28–3.28).

Conclusions:

We found no sex-based differences in risk of perioperative stroke/death among patients ≥80 years of age undergoing transfemoral CAS. Our study validates previous studies showing a high rate of perioperative complications after transfemoral CAS in octogenarians and suggests that the decision to use this technology in older patients should be determined by patients’ anatomic and medical risk factors irrespective of sex.

Transfemoral carotid artery stenting (CAS) has been extensively studied as an alternative to carotid endarterectomy (CEA) for patients with symptomatic carotid stenosis who may be at high risk for CEA because of unfavorable anatomy or medical reasons.¹ Owing to the less invasive nature of CAS compared with CEA, transfemoral CAS initially seemed particularly promising for carotid revascularization in older adults. However, in the lead-in phase of the multicenter Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), octogenarians undergoing CAS had a higher rate of stroke and death during the 30-day periprocedural period than those undergoing CEA.² Similar results have been replicated in subsequent studies,^3,4 thereby tempering the broad adoption of transfemoral CAS as an alternative to CEA in the older population.

There is also substantial variation in the outcomes of transfemoral CAS by sex.^5,6 In CREST, the rate of periprocedural stroke, myocardial infarction (MI), or death was significantly higher with CAS vs CEA in women (8.9% vs 6.7%) but not in men (6.2% vs 6.8%),⁵ implying that men may benefit more from CAS.⁷ These findings are contradictory to conclusions from a systematic review that reported no difference in perioperative outcomes of transfemoral CAS by sex.⁸ Thus, current recommendations for treating men and women with carotid artery stenosis are based on limited and conflicting evidence, with consensus statements calling for further investigation.⁸

Despite the controversial outcomes for transfemoral CAS in older patients and in women compared with men, there are no current data that we know of exploring sex-based differences in the elderly. To address this knowledge gap, we aimed to evaluate sex-based differences in perioperative outcomes after CAS performed in patients 80 years of age and older. Based on previous data suggesting worse outcomes for transfemoral CAS in women compared with men,⁵ we hypothesized that older women would have a higher rate of a composite end point of perioperative stroke or death than older men.

METHODS

Patient cohort.

We performed a retrospective review of data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) targeted vascular module for CAS.⁹ The ACS NSQIP is a nationally validated database that includes data on preoperative, intraoperative, and 30-day postoperative outcomes.¹⁰ The targeted vascular module contains additional carotid disease and carotid artery revascularization-specific patient characteristics and outcomes selected by vascular surgeons. This project was approved by the Institutional Review Board. Informed consent was not obtained because the data were deidentified and publicly available.

We identified all patients aged ≥80 years who underwent transfemoral CAS between January 1, 2011, and December 31, 2017. Patients with total ipsilateral carotid occlusions (n = 15), those <80 years of age (n = 793), and those with no documentation of whether an embolic protection device was used (n = 2) were excluded. Baseline characteristics including demographics (age, race), comorbidities (body mass index, hypertension, diabetes, coronary heart disease, chronic obstructive pulmonary disease, smoking status, dialysis dependence), pertinent preoperative medication (aspirin, statin, beta blocker), and functional status before surgery (independent, partially dependent, totally dependent) were compared for male vs female patients. Of note, age was divided into three tertiles (80–84 years, 85–89 years, and ≥90 years) rather than a continuous variable because NSQIP classifies all patients ≥90 years of age into a single group.

Relevant carotid disease characteristics including degree of ipsilateral and contralateral carotid artery stenosis on presentation and symptomatic status were also compared for men vs women. Symptomatic carotid artery stenosis was defined as a history of transient ischemic attack, stroke in the ipsilateral hemisphere, or amaurosis fugax as reported in the NSQIP. Finally, we evaluated technical considerations including procedural urgency, anesthesia type (general/intravenous sedation vs local/nerve block), use of an embolic protection device, and total operative time. All variables were defined according to the NSQIP data dictionary.¹¹

Exposures and outcomes.

The primary exposure for our study was patient sex (male vs female). We also considered symptomatic status as a secondary exposure variable because of the well-described differences in transfemoral CAS outcomes for symptomatic vs asymptomatic patients.¹²

The primary outcome of the study was a composite end point of any stroke or death occurring within 30 days of the procedure. The primary outcome was limited to 30 days because that is the follow-up provided by the NSQIP database. Secondary outcomes examined included stroke, MI, and death as individual end points as well as postoperative length of stay (LOS) in the hospital.

Statistical analysis.

We compared perioperative outcomes for men vs women ≥80 years of age undergoing transfemoral CAS. Continuous variables were reported as means ± standard deviation; categorical variables were reported as frequencies with percentages. Univariate analyses were performed using Student t-tests and χ² tests for continuous and categorical variables, respectively. We compared all primary and secondary outcomes for men vs women overall as well as stratified by symptomatic status.

Bivariate logistic regression analyses were then used to assess for the association of all baseline characteristics, carotid disease characteristics, and technical considerations with the primary outcome (ie, stroke or death). Multivariable logistic regression analysis was then used to evaluate the independent association of patient sex with the primary outcome. All covariates found to have P < .05 on bivariate analysis were included in the model.

Finally, we performed an additional analysis comparing crude rates for the composite outcome for CAS vs CEA for men and women to better understand the utility of CAS in older patients.

All statistical analyses were performed using Stata/SE version 15 (StataCorp LLC, College Station, Tex). A P value <.05 was considered statistically significant.

RESULTS

Study cohort.

Overall, 143 patients ≥80 years of age underwent transfemoral CAS during the study period, including 95 men (66.4%) and 48 women (33.6%). There were no significant differences for men vs women in terms of age, race (88.0% vs 85.4% white), or body mass index (mean, 27.2 ± 5.3 kg/m² vs 27.0 ± 5.6 kg/m²; all, P ≥ .24; Table I). Comorbidities were also similar for men vs women (Table I), with no significant differences in hypertension (79.0% vs 87.5%), diabetes (13.7% vs 12.5%), chronic obstructive pulmonary disease (13.7% vs 12.5%), coronary heart disease (4.2% vs 6.3%), or hemodialysis (1.1% vs 4.2%) between groups (all, P ≥ .21). The majority of patients were independent (91.6% vs 91.7%) and taking an aspirin (94.7% vs 97.9%) and statin (80.0% vs 83.3%) at baseline (all, P ≥ .37).

Table I.

Baseline characteristics of male vs female patients ≥80 years of age undergoing transfemoral carotid artery stenting (CAS)

Variable	Male (n = 95)	Female (n = 48)	P value
Demographics
Age, years			.24
80–84	61 (64.2)	28 (58.3)
85–89	25 (26.3)	12 (25.0)
≥90	8 (8.4)	8 (16.7)
Race			.66
White	81 (88.0)	41 (85.4)
Black	4 (4.4)	3 (6.3)
Hispanic	5 (5.4)	3 (6.3)
Other	2 (2.2)	1 (2.1)
Comorbidities
Body mass index, kg/m2	27.2 ± 5.3	27.0 ± 5.6	.84
Hypertension	75 (79.0)	42 (87.5)	.21
Diabetes	13 (13.7)	6 (12.5)	.51
COPD	13 (13.7)	6 (12.5)	.84
Coronary heart disease	4 (4.2)	3 (6.3)	.59
Current smoking	7 (7.4)	5 (10.4)	.54
Hemodialysis	1 (1.1)	2 (4.2)	.22
Functional status before surgery			1.0
Independent	87 (91.6)	44 (91.7)
Partially dependent	2 (2.1)	1 (2.1)
Totally dependent	6 (6.3)	3 (6.3)
Preoperative medications
Aspirin	90 (94.7)	47 (97.9)	.37
Statin	76 (80.0)	40 (83.3)	.63
Beta blocker	56 (59.6)	26 (54.2)	.54
Disease characteristics
Degree of ipsilateral stenosis
Moderate (50%–79%)	27 (28.4)	18 (37.5)	.27
Severe (80%–99%)	68 (71.6)	30 (62.5)
Symptomatic	29 (30.9)	14 (29.2)	.84
Amaurosis fugax	9 (9.6)	1 (2.1)
Transient ischemic attack	19 (20.2)	10 (20.8)
Ipsilateral stroke	1 (1.1)	3 (6.3)
Degree of contralateral stenosis			.20
None (<50%)	65 (68.4)	29 (60.4)
Moderate (50%–79%)	22 (25.9)	14 (31.8)
Severe (80%–99%)	8 (9.4)	5 (11.4)
Technical details
Emergent status	5 (5.3)	1 (2.1)	.37
Anesthesia
Local/regional	1 (1.1)	3 (6.3)	.08
General/sedation	93 (98.9)	45 (93.8)	.49
Use of embolic protection device	72 (76.6)	28 (68.0)	.18
Total operation time, minutes	93.9 ± 45.0	95.2 ± 48.2	.85

COPD, Chronic obstructive pulmonary disease.

Categorical variables are presented as number (%). Continuous variables are presented as mean ± standard deviation.

There were no significant differences in carotid disease characteristics between men and women, including ipsilateral disease severity (severe [80%−99%] stenosis, 71.6% vs 62.5%), high-risk anatomic features (32.6% vs 45.8%), and contralateral disease severity (severe stenosis, 9.1% vs 11.4%; all, P ≥ .12; Table I). There was also no significant difference in the proportion of patients with symptomatic carotid artery disease between groups (30.9% vs 29.2%; P = .84). Operative variables were also similar between men and women, including emergent status (5.3% vs 2.1%; P = .37), use of an embolic protection device (76.6% vs 68.0%; P = .18), and total operative time (93.9 ± 45.0 minutes vs 95.2 ± 48.2 minutes; P = .85).

Univariate outcomes.

The composite outcome of perioperative stroke/death occurred in 8 of 143 patients overall (5.6%), including stroke in 5 patients (3.5%) and death in 4 patients (2.8%). Thirty-day stroke/death rates were similar for men and women (6.4% vs 4.2%; P = .59) and did not significantly differ when stratified according to symptomatic (6.9% vs 7.1%; P = .98) and asymptomatic (6.2% vs 2.9%; P = .49) status (Table II).

Table II.

Perioperative outcomes comparing male vs female patients ≥80 years of age undergoing transfemoral carotid artery stenting (CAS) overall and stratified by symptom status

	All patients			Symptomatic patients			Asymptomatic patients
30-Day outcome	Male (n = 95)	Female (n = 48)	P value	Male (n = 29)	Female (n = 14)	P value	Male (n = 66)	Female (n = 34)	P value
Stroke	4 (4.3)	1 (2.1)	.51	0 (0)	0 (0)	.15	4 (6.2)	1 (2.9)	.49
MI	3 (3.2)	3 (6.3)	.38	1 (3.5)	1 (7.1)	.59	2 (3.0)	2 (5.9)	.49
Death	3 (3.2)	1 (2.1)	.71	2 (6.9)	1 (7.1)	.98	1 (1.5)	0 (0)	.47
Composite stroke/death	6 (6.4)	2 (4.2)	.59	2 (6.9)	1 (7.1)	.98	4 (6.2)	1 (2.9)	.49

MI, Myocardial infarction.

All data are presented as number (%).

Secondary perioperative outcomes including individual stroke (4.3% vs 2.1%), MI (3.2% vs 6.3%), and death (3.2% vs 2.1%) outcomes also did not significantly differ for men vs women (all, P ≥ .38). Mean hospital LOS was 3.6 ± 5.7 days for men vs 3.3 ± 4.0 days for women (P = .19).

Bivariate and multivariable analyses.

We performed a bivariate analysis assessing the association of all demographic, comorbidity, and carotid artery disease characteristics with the primary study outcome (Table III). Emergent need for operation was associated with a higher risk of 30-day stroke/death (odds ratio [OR], 26.2; 95% confidence interval [CI], 4.19–163.8), whereas use of an embolic protection device was protective (OR, 0.12; 95% CI, 0.02–0.63). Female sex (OR, 0.64; 95% CI, 0.12–3.29) and symptomatic disease (OR, 1.03; 95% CI, 0.25–4.29) were not associated with composite stroke/death on bivariate analysis.

Table III.

Bivariate and multivariable logistic regression analyses assessing the association of covariates of interest with the composite outcome of 30-day stroke/death after transfemoral carotid artery stenting (CAS) in patients ≥80 years of age

	Bivariate		Multivariable
Variable	OR (95% CI)	P value	OR (95% CI)	P value
Demographics
Female sex	0.64 (0.12–3.29)	.59	0.81 (0.28–3.28)	.48
Age (per year)	1.08 (0.87–1.34)	.48
White race (vs nonwhite)	0.41 (0.08–2.23)	.30
Comorbidities
BMI (per kg/m2)	0.90 (0.76–1.06)	.21
Hypertension	0.35 (0.08–1.55)	.17
Diabetes	0.39 (0.07–2.21)	.29
Current smoking	0.75 (0.09–6.28)	.79
Hemodialysis	9.43 (0.76–116.9)	.08
Preoperative medications
Aspirin	0.27 (0.03–2.65)	.26
Statin	0.69 (0.13–3.61)	.66
Beta blocker	0.42 (0.10–1.84)	.25
Disease characteristics
Ipsilateral severe stenosis	0.91 (0.56–1.49)	.72
Symptomatic status	1.03 (0.25–4.29)	.97
Technical details
Emergent status	26.2 (4.19–163.8)	<.001	20.3 (2.25–183.3)	.001
General/sedation anesthesia	1.34 (0.57–3.13)	.50
Use of embolic protection device	0.12 (0.02–0.63)	.01	0.35 (0.02–0.63)	.03

BMI, Body mass index; CI, confidence interval; OR, odds ratio.

Based on multivariable analysis accounting for sex, procedural urgency, and use of an embolic protection device (Table III), independent factors associated with periprocedural stroke/death included emergent vs elective status (adjusted OR [aOR], 20.3; 95% CI, 2.25–183.3) and failure to use an embolic protection device (aOR, 2.86; 95% CI, 1.59–50.0). Female sex was not significantly associated with the primary outcome after risk adjustment (aOR, 0.81; 95% CI, 0.28–3.28).

Comparison of CAS vs CEA outcomes.

During the study period, 5147 patients ≥80 years of age underwent CEA, including 3030 men (58.9%) and 2117 (41.4%) women. The composite outcome of perioperative stroke/death occurred in 3.2% of men and 2.9% women undergoing CEA compared with 6.4% of men and 4.2% of women undergoing transfemoral CAS (P = .09 and .62, respectively).

DISCUSSION

In this retrospective national cohort study of octogenarians undergoing transfemoral CAS, we studied whether periprocedural outcomes differed by sex. We found no difference in the composite outcome of stroke or death within 30 days of transfemoral CAS for male vs female octogenarians (6.4% vs 4.2%). This finding persisted after adjustment for symptomatic status, procedural urgency, and use of an embolic protection device. Overall, our data suggest that perioperative morbidity after transfemoral CAS is high among patients ≥80 years of age and that the use of this technology in the elderly should be determined by patients’ anatomic and medical risk factors irrespective of sex.

The perioperative event rates for transfemoral CAS in octogenarians that we report are similar to the results of other studies^2–4 and higher than the event rates reported in the general population. Octogenarians in our study had a rate of periprocedural stroke or death of 5.6%, which is somewhat lower than the results from a meta-analysis by Howard et al,³ which reported an 11% periprocedural stroke and death rate after CAS in symptomatic patients ≥80 years of age from four randomized controlled trials of the Carotid Stenosis Trialists’ Collaboration. In contrast, nonoctogenarian patients undergoing transfemoral CAS have periprocedural adverse event rates ranging from 1.7% to 9%, depending on the age range and symptomatic status of the population being studied.^2–4 In a large prospective observational study by Stanziale et al,⁴ the authors reported that perioperative stroke, MI, or death occurred in 3.4% of patients <80 years of age compared with 9.2% of patients aged ≥80 years. Taken together, our data and previous data on this topic confirm that perioperative morbidity after transfemoral CAS occurs more frequently among octogenarians than would be expected in the general population.

We found no significant differences in transfemoral CAS outcomes among octogenarians based on sex. This finding was somewhat surprising, given the prior controversy on this topic.^5–8 The CREST trial suggested that women may have a greater risk of periprocedural stroke, MI, or death at 30 days after CAS compared with men (6.8% in women compared with 4.3% in men), driven largely by an increased periprocedural risk of stroke in women.⁵ This could possibly be due to the larger mean particle size that has reportedly been captured in embolic protection devices after transfemoral CAS in women.¹³ In our study, the perioperative stroke rates were somewhat lower in women compared with men (2.1% vs 4.3%), suggesting that the sex-based differences in outcomes that were observed in CREST may not be applicable to older patients. Consistent with this notion, the results from CREST were not statistically significant after adjustment for age and symptomatic status.⁵ Importantly, a systematic review from Touze et al⁸ that included both observational and randomized controlled trial data has also shown that the risk of perioperative transfemoral CAS events is not related to the patient’s sex but rather depends on age, hypertension, and history of coronary heart disease. Schmid et al¹⁴ also recently reported that age rather than sex appears to be correlated to risk of in-hospital stroke or death after CAS, supporting our findings that sex is not associated with worse outcomes after transfemoral CAS performed in patients ≥80 years of age. Ultimately, our data add credence to the idea that the patient’s age and disease factors, rather than sex, should determine the most appropriate revascularization approach.

Notably, we did not find a significant difference in the rate of periprocedural stroke or death after CAS vs CEA in older patients. This was somewhat surprising as favorable outcomes with CEA over CAS in octogenarians have been previously reported by CREST² and other studies.^3,4 Importantly, stroke/death occurred in 5.6% of patients after CAS in our study compared with 3.1% of patients after CEA. Given that the primary aim of our study was to compare sex-related outcomes after CAS, our data were not powered to detect a difference in outcomes according to revascularization approach. The low number of CAS procedures performed in older patients compared with CEA (143 vs 5147) speaks to the widespread and appropriate adoption of CEA in this population.

We did find that emergent case status and failure to use an embolic protection device were associated with higher rates of periprocedural stroke or death after multivariable adjustment. These findings are consistent with the literature.^15–18 Urgent and emergent procedures have previously been shown to increase the perioperative rate of stroke or death after transfemoral CAS by fivefold in the general population.¹⁷ We found an even higher risk of poor outcomes after emergent CAS procedures in our study (OR, 16.7), which may reflect the fact that older patients tend to do worse than younger patients after emergent procedures.^19–21 It was surprising that only 70% of patients underwent CAS with an embolic protection device, given that use of an embolic protection device during transfemoral CAS is well supported^15,16,18 and has been shown to lower minor and major periprocedural stroke events by 3.2% and 0.8%, respectively.¹⁸ Perhaps the low rate in our study was due to cases performed earlier in the study period or for anatomic reasons. Notably, Piazza et al²² reported an association between embolic filter debris load and periprocedural stroke, with filter loads >12.5% being the optimal cutoff for the association of clinically relevant perioperative ischemic events. Based on multivariable analysis, patient age >75 years was associated with a 2.5 times higher risk of achieving a 12.5% filter load, further reaffirming that older patients may have a higher risk of poor outcomes after transfemoral CAS because of the nature of their atherosclerotic disease.

Interestingly, we did not find that symptomatic status was associated with worse periprocedural outcomes in our study. It is generally recognized that patients with symptomatic carotid artery stenosis have a higher risk of perioperative stroke after transfemoral CAS than asymptomatic patients do.¹² We may have been underpowered to identify statistically significant differences in our analysis because only 43 patients (30%) underwent CAS for symptomatic carotid artery disease. It is somewhat concerning that less than one-third of octogenarians in the NSQIP vascular module underwent CAS for symptomatic disease, given that the Medicare guidelines specify that CAS should be used only for symptomatic disease except among patients participating in a clinical trial or postapproval study.²³ We plan to investigate this phenomenon further in additional work through the Vascular Quality Initiative.

Finally, it is notable that although there was a similar LOS between sexes, octogenarians were hospitalized for an average of 3.5 days after CAS. Badheka et al²⁴ reported an average LOS of 2.5 days in their study of adults (mean age, 71 years) undergoing CAS using the National Inpatient Sample. This suggests a higher utilization of resources in octogenarians undergoing transfemoral CAS compared with the general population, which may be better understood through studies about the cost-effectiveness of CAS in the elderly.

Our study has several limitations that merit discussion. We used retrospective observational data and thus cannot comment on causative associations. Our study sample was limited in size, although we did use a national cohort. The use of the ACS NSQIP database limited our ability to comment on age as a continuous variable as all patients ≥90 years of age were classified into a single age group. In addition, the NSQIP reports outcomes only out to 30 days, so we were limited in our ability to examine long-term outcomes after CAS. We also do not have data on how many patients underwent CAS for recurrent carotid artery stenosis, which may have affected outcomes. Finally, we do not have data on the outcomes of transcarotid artery revascularization in the older population, which has recently been shown to have promising outcomes compared with transfemoral CAS.²⁵

CONCLUSIONS

We found similar 30-day rates of stroke or death for men and women ≥80 years undergoing transfemoral CAS in a national cohort. The higher rate of perioperative events after transfemoral CAS in octogenarians compared with those reported in the general population suggests that the decision to use this technology in older patients should be determined by patients’ anatomic and medical risk factors irrespective of sex.

ARTICLE HIGHLIGHTS.

• Type of Research: Retrospective review of data from the American College of Surgeons National Surgical Quality Improvement Program vascular targeted carotid artery stenting (CAS) module

• Key Findings: Based on data from 143 patients ≥80 years of age undergoing transfemoral CAS, there were no differences in a composite end point of perioperative stroke/death for men (6.4%) vs women (4.2%).

• Take Home Message: There was a high rate of perioperative complications after transfemoral CAS in octogenarians. The decision to use this technology in older patients should be determined by patients’ anatomic and medical risk factors irrespective of sex.