Nurose Karim, MD
Atherosclerotic carotid artery disease (CAD) is responsible for near 10-15% of strokes. Their prevalence increases with age, and there are racial and gender differences. The incidence is highest in Native American people followed by white. African American males and Asian females have the lowest prevalence. The estimated >50% sclerotic CAD prevalence in Caucasian males is 2.3% in their 60s, which increases to 6.0% in 70s and 7.5% in 80s. The corresponding prevalence in women is 2.0%, 3.6% and 5.0% in their 60s, 70s and 80s, respectively. Active smoking, diabetes and hypertension are strongly associated with increased carotid intima and media thickness and carotid plaque. Other cardiovascular risk factors include metabolic syndrome and hypertriglyceridemia. The age-related changes in the intima progresses faster in women after age 60 secondary to menopause, which causes stiffer arteries and hypertension.
It is a well-known fact that the ipsilateral stroke risk increases with the degree of stenosis which is independent of gender. The outcome of stroke and CAD is worse in women due to several reasons including disease pathophysiology, role of estrogen and other sex hormones, access to care, seeking medical attention, provider bias, and socioeconomic status. Women tend to present with uncommon symptoms including incontinence, nausea, loss of consciousness, and difficulty swallowing, which may lead to delay in diagnosis and treatment. The cerebral ischemic response is also thought to be different in men vs women.
Results of Carotid Intervention in Women:
- Carotid Endarterectomy: The major trials in 1990s for carotid revascularization studies including the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) did not analyze data by gender; therefore, providing sex-specific recommendations for treatment of both symptomatic and asymptomatic carotid stenosis in women is challenging. The only trial that recruited a significant number of female patients and reported the surgical results in both sexes individually was the Asymptomatic Carotid Atherosclerosis Trial (ACAS).
- Asymptomatic Disease: In the ACAS study, 281 female patients who underwent CEA had higher perioperative complication rates- stroke or death (3.6%) which was doubled than males and the benefits of CEA over current best medical therapy were less robust, although not statistically significant. The five-year absolute risk reduction was only 1.4% in women vs 8% in men, and 5-year event reduction rate was 17% in women vs 66% in men (not statistically significant). In patients with no perioperative event, the 5-year stroke reduction risk was 56% in women vs 79% men.
The (Asymptomatic Carotid Surgery Trial) ACST-1 enrolled 34% of females which also reported that women had a lower absolute risk reduction (4.1%) of stroke with CEA as compared to medical therapy alone at five years compared to men (8.2%). Meta-analysis from ACAS and ACST showed benefit of CEA along with medical management in reducing 5-year risk of any stroke or perioperative death in men, but not in women, compared to medical management alone. Interestingly, in 10-year follow up, the net benefit of CEA in stroke prevention over medical management was maintained long term in both men and women up to age 75 and was statistically significant.
The Carotid Revascularization Endarterectomy versus Stenting (CREST) trial compared CEA with carotid stenting in both symptomatic and asymptomatic patients and analyzed the outcome by sex differences. In females undergoing CEA, no statistically significant differences were noted in the risk of perioperative stroke (2.2% vs. 2.4%) or stroke/death (2.2% vs. 2.4%) as compared to males. The four-year outcome of stroke or death for female patients undergoing CEA were similar to male patients (5.0% vs. 4.5%). For asymptomatic patients undergoing CEA in CREST, no differences were found in the risk of perioperative stroke or death between female and male patients (1.6% vs. 1.3%), or in the four-year risk of stroke or death (2.7% vs. 2.7%). Similarly, for symptomatic patients undergoing CEA, no significant differences were noted in the risk of perioperative stroke or death between female and male patients (2.7% vs. 3.5%), or in the four-year risk of stroke or death (6.9% vs. 6.2%).
The recent ASCT-2 trial included 3625 asymptomatic patients assigned to CAS and CEA with 5-year follow up. Overall, the conclusion from all these trials demonstrated decreased efficacy in stroke prevention from CEA in asymptomatic women when compared to men.
Specific Sex-Related Carotid Artery Features:
The size of internal carotid artery is smaller in women, making it less compliant and predisposing to iatrogenic injuries and early post-operative thrombosis. As opposed to primary closure, patch angioplasty is recommended in women. Women also have a higher restenosis risk. Eversion endarterectomy is another technique preferred in women. Interestingly, carotid plaques in women have more smooth muscle cells, decreased protease activity and lower risk of rupture. The timings of treatment in symptomatic women are crucial. NASCET and ECST showed that early treatment (CEA) within two weeks of stroke/TIA caused an absolute stroke risk reduction of 41.7%. This benefit was reduced to 6.6% if performed at 2-4 weeks following symptoms and there was no benefit and, in fact, harm if CEA was performed after 4-12 weeks of symptoms. On the other hand, males have a constant absolute risk reduction regardless of the timing of treatment.
Transfemoral carotid artery stenting (TF-CAS) and Transcarotid Artery Revascularization (TCAR):
In TCAR, a stent is placed through direct access to the common carotid artery, thus avoiding passage of catheters through the aortic arch and permitting neuroprotection using proximal clamping and reversed flow. Embolic protection is achieved through flow reversal with filtering between the common carotid artery and the femoral vein. The results from the trials have shown mixed results, anywhere from no gender-specific differences to worse outcomes in women including stroke or death within 30 days of procedure. Subgroup analysis of the CREST trial showed higher periprocedural stroke rate in TF-CAS treated women compared to CEA. However, there were no significant differences in the primary endpoint. The available carotid stents are designed for internal carotid arteries of 4mm diameter or larger and for common carotid arteries of 6mm diameter of larger. Studies have shown that in women, the luminal diameter gets narrower, thus excluding them from being the candidates for CAS.
Choice of Appropriate Carotid Intervention in Women:
The most recent guidelines from the Society for Vascular Surgery (SVS) on the management of extracranial cerebrovascular disease recommend:
- Asymptomatic extracranial carotid stenosis with <60% stenosis or symptomatic patients with <50% stenosis should be treated medically.
- Asymptomatic patients with >70% stenosis, should be treated surgically (CEA, TCAR or TF-CAS), if their life expectancy is 3-5 years and pre-operative stroke and mortality risk is <3% or less. The choice of which surgical intervention is preferred depends on surgical risk.
- CEA in symptomatic patients with ≥ 50% stenosis with standard surgical risk.
- TF-CAS in symptomatic patients with ≥ 50% stenosis with difficult anatomy secondary to a tracheal stoma and fibrosis or scar tissue related to prior neck surgery or irradiation.
- TCAR in symptomatic patients with high carotid lesions and other high-risk anatomic or physiologic cases.
- CAS is preferred over CEA in patients with >50% stenosis and multiple medical comorbidities (CAD, CHF).
- Asymptomatic patients with high surgical risk should be managed medically.
- There is insufficient data to recommend TF-CAS as primary treatment option for asymptomatic patients with >70% stenosis.
The SVS also provided recommendations specific for female patients, which are as follows:
- Patchy angioplasty or eversion endarterectomy preferred over conventional CEA with primary closure. It decreases the incidence of re-stenosis.
- For patients at high risk of restenosis after CEA or CAS (multiple vascular risk factors), surveillance with repeat Doppler carotid ultrasound is recommended every 6 months until stability.
Conclusion:
Genetic and environmental factors have a role in the stroke outcome, which is different in women as compared to men. In general, women experience more disability and poor outcome from stroke due to several factors including longer life expectancy, less access to health care and treatment bias. Due to females being underrepresented in many clinical trials, the actual data regarding the management of carotid stenosis is perplexing. It is anywhere from worse periprocedural outcomes to similar risk in both genders. Therefore, the choice of a carotid revascularization is to be customized individually considering multiple factors including age, comorbidities, neck anatomy and plaque morphology.
