1. Asymptomatic Carotid Atherosclerosis Study (ACAS): This study, published in 1995, demonstrated that carotid endarterectomy is beneficial for patients with asymptomatic carotid stenosis of 60% or more. It showed a reduction in the 5-year risk of ipsilateral stroke from 11% to 5.1%. However, the surgery was only beneficial if the perioperative morbidity and mortality were below 3%.
2. Asymptomatic Carotid Surgery Trial (ACST): Published in 2004, this study further confirmed the benefits of CEA in patients with asymptomatic carotid stenosis. It found that CEA led to a significant reduction in the risk of stroke over a 10-year period.
3. North American Symptomatic Carotid Endarterectomy Trial (NASCET): This study demonstrated that CEA was beneficial for patients with symptomatic carotid stenosis of 70% or more. It showed a reduction in the 2-year risk of ipsilateral stroke from 26% to 9%.
4. European Carotid Surgery Trial (ECST): This trial also showed a significant benefit of CEA in patients with symptomatic carotid stenosis of 70% or more.
5. Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): This was a large, multicenter randomized trial comparing CEA and CAS in both symptomatic and asymptomatic patients. The results showed that both procedures were comparably safe and effective. However, CAS was associated with a higher risk of stroke, while CEA was associated with a higher risk of myocardial infarction.
6. International Carotid Stenting Study (ICSS): This trial compared CAS and CEA in patients with symptomatic carotid stenosis. It found that CAS was associated with a higher risk of stroke or death within 120 days of the procedure compared to CEA.

The Asymptomatic Carotid Atherosclerosis Study (ACAS) was a landmark study that changed the management of patients with asymptomatic carotid stenosis. Published in the New England Journal of Medicine in 1995, it was a randomized controlled trial involving 1,662 patients with asymptomatic carotid stenosis of 60% or more.

Patients in the study were randomized to one of two groups: medical management alone, which consisted of aspirin and aggressive risk factor management, or medical management plus carotid endarterectomy (CEA), a surgical procedure to remove the atherosclerotic plaque from the carotid artery.

The primary endpoint of the study was the occurrence of ipsilateral stroke or perioperative stroke or death. After a mean follow-up of 2.7 years, the study found a significant reduction in the risk of these outcomes in the CEA group.

The study’s main findings were:

1. Stroke Risk Reduction: The trial found a significant reduction in the risk of stroke in patients undergoing CEA. The five-year risk of ipsilateral stroke (a stroke occurring on the same side as the stenosis) or perioperative stroke or death was 5.1% in the CEA group, compared to 11.0% in the medical management group. This represented a relative risk reduction of about 53% with CEA.
2. Perioperative Morbidity and Mortality: The study also found that the benefits of CEA were apparent only if the perioperative morbidity and mortality were less than 3%. This highlighted the importance of performing CEA in centers with a low perioperative complication rate.
3. Gender Differences: The study did not find a statistically significant difference in the benefit of CEA between men and women. This was an important finding, as some earlier studies had suggested that CEA might be less beneficial in women.
4. Importance of Risk Factor Management: The study emphasized the importance of aggressive risk factor management in all patients with carotid stenosis, regardless of whether they undergo CEA.

The ACAS trial provided strong evidence in favor of CEA for patients with asymptomatic carotid stenosis of 60% or more. However, it also emphasized the importance of careful patient selection and high-quality surgical care. Since its publication, the results of ACAS have guided the management of patients with asymptomatic carotid stenosis.

However, like all studies, it had limitations and faced some criticisms. Here are a few:

1. Patient Selection: Some critics noted that the ACAS included a highly selected group of patients who were at low risk for surgical complications. The surgeons involved in the study were also carefully selected and had to demonstrate low complication rates. Therefore, the results might not be generalizable to all patients and all settings.
2. Medical Management: At the time of the ACAS, the standard of medical management for stroke prevention was not as advanced as it is today. Treatments such as statins and modern antihypertensives were not part of the standard medical management during the study. Critics argue that better medical management might reduce the relative benefit of surgery.
3. Low Absolute Risk Reduction: Although the relative risk reduction with CEA was impressive, the absolute risk reduction was relatively small (around 5.9% at five years). Some critics argued that this small absolute benefit might not justify the risks and costs of surgery for all patients.
4. Lack of Long-Term Follow-Up: The ACAS had a relatively short follow-up period (average of 2.7 years), and it was unclear whether the benefits of CEA would persist in the long term.
5. Lack of Imaging Techniques: Modern imaging techniques, which provide better risk stratification for stroke, were not available at the time of the ACAS. Some have criticized the study for not considering plaque characteristics, which can influence stroke risk.

The Asymptomatic Carotid Surgery Trial (ACST) was a randomized controlled trial designed to assess the efficacy of carotid endarterectomy (CEA) for the prevention of stroke in patients with asymptomatic carotid stenosis. The trial included 3,120 patients from 126 centers in 30 countries, making it one of the largest trials of its kind.

Patients with asymptomatic carotid artery stenosis of at least 60% were randomized to receive either immediate carotid endarterectomy plus medical therapy or medical therapy alone. The primary endpoint was the occurrence of any stroke or death from any cause during the follow-up period.

The main findings of the ACST were as follows:

1. Risk Reduction: At five years, the risk of any stroke was 6.4% in the surgery group compared with 11.8% in the medical management group. This represents a significant reduction in the risk of stroke with CEA.
2. Risk of Disabling Stroke or Death: At five years, the risk of disabling stroke or death was 3.4% in the surgery group compared with 6.4% in the medical management group. Again, this represents a significant reduction with CEA.
3. Perioperative Risk: Among patients in the surgery group, there was a 3.1% risk of stroke or death within 30 days of CEA.
4. Long-Term Follow-up: The surgery group continued to have a lower risk of stroke during the entire follow-up period, which extended up to 10 years for some patients. The risk of any stroke or perioperative death at 10 years was 17.9% in the surgery group compared with 28.3% in the medical management group.
5. Benefit Across Subgroups: The benefit of CEA was consistent across different age groups and both sexes. For example, the risk of any stroke or perioperative death at 5 years was 5.9% in men and 7.2% in women in the surgery group, compared with 12.5% in men and 10.8% in women in the medical management group.

The Asymptomatic Carotid Surgery Trial (ACST) provided valuable insights and made a significant contribution to our understanding of the management of asymptomatic carotid stenosis. However, like all studies, it faced some criticisms and limitations. Here are a few:

1. Patient Selection: Similar to the ACAS trial, some critics have pointed out that the ACST included a highly selected group of patients who were at low risk for surgical complications. Therefore, the results might not be generalizable to all patients and all settings.
2. Medical Management: The ACST trial was conducted at a time when medical management for stroke prevention was not as advanced as it is today. Treatments such as statins and modern antihypertensives were not part of the standard medical management during the study. Critics argue that better medical management might reduce the relative benefit of surgery.
3. Perioperative Morbidity and Mortality: Critics have argued that the perioperative morbidity and mortality in the ACST trial were higher than in some contemporary series, which might have influenced the outcome.
4. No Blinding: As with most surgical trials, the ACST trial was not blinded. This means that the doctors and patients knew which treatment they were receiving, which could introduce bias.
5. Outdated Surgical Technique: Some critics have pointed out that the surgical techniques used in the ACST trial are not reflective of current practice. For instance, the use of patch angioplasty during carotid endarterectomy, which is now common practice, was not routine during the ACST trial.
6. Lack of Contemporary Imaging Techniques: Modern imaging techniques, which provide better risk stratification for stroke, were not available at the time of the ACST. Some have criticized the study for not considering plaque characteristics, which can influence stroke risk.

The North American Symptomatic Carotid Endarterectomy Trial (NASCET) was a landmark study conducted to assess the efficacy of carotid endarterectomy (CEA) in patients with symptomatic carotid artery stenosis.

NASCET was a randomized controlled trial that compared medical management alone to medical management plus CEA in patients with recent symptoms of carotid artery stenosis. The trial included patients with both moderate (50-69%) and high-grade (70-99%) stenosis.

Here are the main findings of the NASCET:

1. High-Grade Stenosis: For patients with high-grade stenosis (70-99%), the two-year risk of ipsilateral stroke was 26% in the medical management group compared to 9% in the CEA group, translating to an absolute risk reduction of 17% and a relative risk reduction of 65% with CEA. This benefit was significant and favored the use of CEA for high-grade stenosis.
2. Moderate Stenosis: For patients with moderate stenosis (50-69%), the benefit was less pronounced. The five-year risk of ipsilateral stroke was 22.2% in the medical management group and 15.7% in the CEA group, resulting in an absolute risk reduction of 6.5% and a relative risk reduction of 29%. The study concluded that for this group, the decision for CEA should be individualized based on patient-specific factors such as age, sex, and comorbidities.
3. Low-Grade Stenosis: For patients with low-grade stenosis (<50%), there was no significant benefit from CEA.
4. Perioperative Risk: In both the moderate and high-grade stenosis groups, the benefit from CEA was only apparent if the perioperative stroke and death rate was below 6%.

In summary, the NASCET trial provided evidence supporting the use of CEA in patients with symptomatic carotid stenosis, particularly in those with high-grade stenosis. It also emphasized the importance of maintaining a low perioperative complication rate to realize the benefits of the procedure.

Limitations of the study:

1. Patient Selection: The NASCET trial included a select group of patients who were at lower risk for surgical complications. Thus, the results might not be fully generalizable to a broader patient population, particularly those at higher surgical risk due to age or comorbidities.
2. Surgical Expertise: The surgeons involved in the trial had demonstrated low complication rates, which may not reflect the average surgical outcomes in the general community. This factor may affect the generalizability of the trial’s results.
3. Medical Management: The standard of medical therapy has evolved considerably since the NASCET trial. Critics argue that the relative benefit of surgery might be less today, given the advancements in stroke prevention with treatments such as statins and more potent antiplatelet therapies.
4. Absence of Modern Imaging Techniques: The NASCET trial was conducted before the routine use of advanced imaging techniques, which can provide a more detailed assessment of carotid plaque characteristics. The presence of unstable plaques is now recognized as an important risk factor for stroke, irrespective of the degree of stenosis.
5. Follow-up Period: While the NASCET trial provided strong evidence for the benefit of carotid endarterectomy, the follow-up period was relatively short. Therefore, the long-term risks and benefits of surgery versus medical management remain a topic of ongoing research.
6. Lack of Evaluation of Stenting: The NASCET trial was conducted before the widespread use of carotid artery stenting, another important treatment option for carotid artery stenosis.

The European Carotid Surgery Trial (ECST) was a large, randomized controlled trial that aimed to assess the efficacy of carotid endarterectomy (CEA) in patients with symptomatic carotid stenosis. The ECST, along with the North American Symptomatic Carotid Endarterectomy Trial (NASCET), significantly influenced the management of symptomatic carotid artery stenosis.

The trial included patients with recent symptoms of carotid artery stenosis who were randomized to either immediate surgery (CEA) or deferred surgery.

Here are the main findings of the ECST:

1. Risk Reduction: For patients with severe stenosis (70-99% by the ECST method of measurement), the risk of major stroke or death at 3 years was 26.5% in the deferred surgery group, compared with 15.4% in the immediate surgery group. This translates into a substantial risk reduction with CEA.
2. Benefit in Moderate Stenosis: In patients with moderate stenosis (50-69%), there was also a benefit from CEA, but it was less pronounced than in the severe stenosis group.
3. No Benefit in Mild Stenosis: For patients with mild stenosis (<50%), the trial found no benefit from CEA.
4. Perioperative Risk: The benefit of CEA was most pronounced when the perioperative risk of stroke or death was low. Patients with high perioperative risk did not experience a net benefit from surgery.
5. Long-Term Benefit: The benefits of CEA were not only immediate but also extended over a long-term follow-up period. Patients in the immediate surgery group continued to have a lower risk of stroke over time.

In summary, the ECST provided evidence in favor of CEA for the prevention of stroke in patients with symptomatic carotid stenosis, particularly for those with severe stenosis. However, the benefit of surgery was most apparent when the perioperative risks were minimized. This underscores the importance of careful patient selection and high-quality surgical care in this setting.

Limitations of ECST:

1. Measurement of Stenosis: The ECST used a different method to measure carotid stenosis compared to the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The ECST measured the degree of stenosis against the estimated original diameter of the artery, which can overestimate the severity of stenosis compared to the NASCET method. This difference led to some confusion and made it difficult to compare the results of the two studies directly.
2. Patient Selection: The trial recruited patients who were likely at lower risk for surgical complications. Therefore, the results might not be fully generalizable to a broader patient population, especially those at higher surgical risk due to comorbidities or age.
3. Medical Management: The standard of medical therapy for stroke prevention has evolved considerably since the ECST trial. Critics argue that the relative benefit of surgery might be less with today’s more advanced medical management.
4. High Perioperative Complication Rate: The trial reported a relatively high perioperative stroke and death rate, raising concerns about the generalizability of the findings to settings where lower complication rates might be expected.
5. Absence of Modern Imaging Techniques: The ECST trial was conducted before the routine use of advanced imaging techniques that provide a more detailed assessment of plaque characteristics, which are now recognized as an important risk factor for stroke.
6. Lack of Evaluation of Stenting: The ECST trial was conducted before the widespread use of carotid artery stenting, an alternative to carotid endarterectomy.

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) was a multicenter, randomized controlled trial that compared carotid endarterectomy (CEA) with carotid artery stenting (CAS) in both symptomatic and asymptomatic patients with carotid stenosis.

The trial enrolled 2,502 patients with either symptomatic (recent stroke, transient ischemic attack, or retinal ischemic symptoms) or asymptomatic carotid stenosis. Patients were randomized to undergo either CEA or CAS. The primary composite endpoint was stroke, myocardial infarction (MI), or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization.

1. Equivalence of CAS and CEA: The trial found that CAS and CEA were largely equivalent in terms of the primary composite endpoint. The four-year rate of the primary endpoint events was 7.2% in the CAS group and 6.8% in the CEA group.
2. Periprocedural Outcomes: In the periprocedural period, CAS was associated with a higher risk of stroke, while CEA was associated with a higher risk of MI. Specifically, the rate of stroke was 4.1% for CAS and 2.3% for CEA. The rate of MI was 2.3% for CEA and 1.1% for CAS.
3. Age-related Outcomes: Interestingly, the trial found an effect of age on the outcomes. In patients older than 70, CEA was associated with better outcomes than CAS, primarily due to a higher risk of stroke with CAS. In contrast, in patients younger than 70, the outcomes were similar between the two groups.
4. Long-Term Outcomes: Over the long term (up to 10 years), there were no significant differences in the rates of ipsilateral stroke between the two groups.

In summary, the CREST trial demonstrated largely equivalent outcomes for CEA and CAS in the management of carotid stenosis, although the periprocedural risks differed between the two procedures. The results also highlighted an age-related effect, suggesting that CEA might be a better option for older patients.

Criticisms of the trial:

1. Operator Experience: The interventionalists in the CREST trial were highly experienced in performing CAS, which may not be reflective of the general medical community. This could potentially skew the results in favor of CAS.
2. Patient Selection: The study included both symptomatic and asymptomatic patients, which may have confounded the results. Some critics argue that the trial should have been stratified based on symptom status.
3. Endpoint Selection: The primary composite endpoint included myocardial infarction (MI), which critics argue may not be as clinically relevant as stroke in this patient population. Critics argue that including MI in the composite outcome could potentially mask differences in stroke rates between the two groups.
4. Age Cut-Off: The age-related outcomes have been critiqued due to the arbitrary cut-off at age 70. Some have argued that this may oversimplify the complex interaction between age and procedure-related outcomes.
5. Follow-Up Period: While the follow-up in CREST was considerable, long-term durability of CAS compared to CEA is still an open question.
6. Modern Medical Management: As with many trials in this field, the medical management strategies for stroke prevention have evolved since the trial was conducted. Critics argue that the relative benefit of surgery and stenting might be less with today’s more advanced medical management.

The International Carotid Stenting Study (ICSS) was a randomized controlled trial that aimed to compare carotid endarterectomy (CEA) to carotid artery stenting (CAS) in patients with symptomatic carotid stenosis.

The trial included 1,713 patients with recent symptoms (within the past 120 days) related to carotid stenosis of 50% or more. The patients were randomly assigned to undergo either CEA or CAS. The primary outcome of the study was the cumulative 120-day risk of stroke, death, or procedural myocardial infarction.

1. Periprocedural Risks: The ICSS found a higher risk of stroke within 120 days of the procedure in the CAS group compared to the CEA group (8.5% vs. 5.2%). There was no significant difference in the rate of myocardial infarction or death between the two groups.
2. Long-Term Outcomes: In terms of long-term outcomes, the 5-year risk of ipsilateral stroke was similar between the CAS and CEA groups.
3. Age-Related Outcomes: There was a trend towards higher periprocedural stroke risk with CAS in older patients, although this difference was not statistically significant.

In summary, the ICSS trial suggested that CEA has a lower periprocedural stroke risk compared to CAS in patients with symptomatic carotid stenosis. However, the long-term stroke risk was similar between the two groups. The results also hinted at a possible age effect, but this finding was less clear-cut compared to the CREST trial.