Carotid Endarterectomy Trial Research Articles

Carotid Artery Stenting Compared to Carotid Endarterectomy Performed Exclusively in a Veteran Population

To evaluate a single center's experience with carotid artery stenting (CAS) and carotid endarterectomy (CEA) performed by vascular surgeons in an entirely veteran population. Data from the Lakeside and Jesse Brown Veterans Affairs Medical Centers (VAMC) from September 1997 to December 2006 were retrospectively reviewed. Indications for CAS or CEA included asymptomatic carotid stenosis >70% or symptomatic stenosis >50%. Demographic data, procedural details, and clinical outcomes are reported. A cohort of 104 patients (98% men) underwent 113 CAS procedures with 100% technical success. Cerebral protection was used in 98% of the procedures. Average age was 70 years (15 patients >or=80 years old); 30% were symptomatic. Previous ipsilateral CEA, neck dissection or irradiation was present in 10.6% of procedures. The 30-day transient ischemic attack, stroke, and death rates were 2.7%, 3.5%, and 0.0% respectively. The 1-year all cause death rate was 6.2%. During the same time period, 79 patients (98% male) underwent 91 CEA procedures. Average age was 67 years (9 patients >or=80 years old); 45% were symptomatic. The 30-day transient ischemic attack, stroke, and death rates were 1%, 2.2%, and 1% respectively. The 1-year all cause death rate was 5.5%. There were no statistically significant differences in outcome within asymptomatic and symptomatic patient groups between CAS and CEA, respectively. CAS is a safe and efficacious alternative for the treatment of carotid artery stenosis in a veteran population and outcomes compare favorably to contemporary CAS and CEA trials. Veterans should be offered CAS as a treatment option for carotid artery stenosis by vascular surgeons or interventionalists who are trained to perform this procedure and have the appropriate resources.

Clinical studies of carotid artery stenting: Why don’t they tell us what we need to know?

Being selected as the 34th President of The New England Society for Vascular Surgery is one of the great honors of my career. My association with this society dates back to meetings at the old Mount Washington Hotel, with 50 or so stalwarts seated on folding chairs in a tiny meeting room with a roll-up screen and a single Kodak carousel projector. In those days, we were a sideshow for the New England Surgical Society. How far we have come! Our growth to independence has mirrored the maturation of our specialty. Witnessing this growth and maturation over the past 25 years has been a great privilege. The treatment of carotid artery disease, and specifically carotid endarterectomy (CEA), has been my major academic interest in vascular surgery, and so I have been more than a little threatened by the rise of carotid artery stenting (CAS). As I am becoming a late-middle-aged dog, new tricks don’t come easily. As I have watched and studied this new procedure, I have become convinced that it has a role in the management of our patients. I simply don’t know what role. Unfortunately, the currently available clinical trials don’t help me much. Why? In this presentation, I want to review with you the current trials of CAS, assess their value and their shortcomings, look at their common features, and finally, explore why they fail to define for us the appropriate role for this new procedure. Any review of the CAS trials should start with a quick history of CEA trials and the evidence basis they provide for the role of endarterectomy in the management of our patients. I will then briefly present the major published registries and trials of CAS. I will summarize the findings of these registries and trials. I will conclude with some reflec-

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial

Carotid endarterectomy in the UK: acceptable risks but unacceptable delays

Carotid endarterectomy (CEA) is of benefit for stroke prevention in the presence of severe carotid stenosis, provided surgical morbidity and mortality are acceptably low. To assess the current performance of CEA in the UK, an interim analysis of 30-day postoperative outcome data, blinded to anaesthetic allocation, from the first 1,001 UK patients randomised in the GALA Trial (multicentre randomised trial of general versus local anaesthesia for CEA) took place and the time from last symptomatic event to surgery was recorded. The 30-day risk of stroke was 5.3%, myocardial infarction (MI) 0.4%, death 1.7%, and stroke, MI or death 6.4%. Median delay between symptoms and surgery was 82 days. These risks are similar to those reported in the large randomised trials of CEA, but current delays to surgery are excessive and must have substantially reduced the benefit of endarterectomy.

The Argument to Support Broader Application of Extracranial Carotid Artery Stent Technology

As new technology becomes available, the stent technique for the extracranial carotid artery continues to evolve into a safer, more effective therapy for stroke prevention. With the availability of embolic protection, improved stent designs, and added endovascular physician experience, outcomes for carotid artery stenting (CAS) now consistently parallel those for carotid endarterectomy (CEA). Although carotid endarterectomy was established as the gold standard for carotid revascularization, the available scientific evidence must continue to be interpreted in the context of further advancements in nearly all related areas of medicine. One multicenter randomized trial and several nonrandomized registries have successfully established the CAS indications for patients with high surgical risk and have provided evidence to support the use of CAS techniques in patients with low surgical risk. Clinicians must continue to improve their understanding of patient-specific factors and conduct research that will refine indications while optimizing current medical therapy and that will integrate CAS and carotid endarterectomy as complementary treatments. Response by LoGerfo p 1610 The outcomes for CAS have been improving over the past 10 years and now appear nearly equivalent to those for CEA. In fact, many historical similarities are seen in the development of these 2 techniques. Although CEA was established as the gold standard for extracranial carotid revascularization, the available scientific evidence must continue to be interpreted in the context of further advancements in nearly all related areas of medicine. The current research comparing CAS and CEA has not shown a clinically robust and statistically significant difference between the 2 treatments. When differences do exist, clinicians must continue to refine patient-specific indications and to conduct further research to understand these complex risk-benefit analyses in the context of advanced medical treatments and complementary revascularization techniques. The following review details the argument to support implementation of CAS technology for athero-occlusive carotid …

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised noninferiority trial

30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised noninferiority trial

Randomized, Controlled Trials

Randomized, Controlled Trials

Assessment of short-term outcomes for protected carotid angioplasty with stents using recent evidence

Carotid artery stenosis is an important risk factor and etiology of stroke. Carotid endarterectomy (CEA) is the gold standard for the treatment of carotid artery stenosis; however, there are potential benefits to adopting the use of carotid artery stenting (CAS) with protection devices. A number of large protected CAS (PCAS) trials are underway, but final results are still several years away. In the interim, numerous PCAS studies have recently been published, and the aim of this study was to combine the published results and examine the outcomes and safety of PCAS. Electronic, manual, and bibliographic searches of PubMed and PreMedline were conducted. Proportion differences were calculated for the periprocedural (30-day) outcomes of any stroke and any stroke or death. More than 400 articles were identified. Only 26 studies met the inclusion criteria, resulting in the inclusion of 2,992 patients treated with PCAS. Within this patient group, the pooled perioperative PCAS rate of any type of stroke was 2.4% +/- 0.3% (95% confidence interval [CI]). The 30-day minor stroke rate was 1.1% +/- 0.2% (95% CI), and the 30-day major stroke rate was 0.6% +/- 0.2% (95% CI). The 30-day mortality rate was 0.9% +/- 0.4% (95% CI). This study demonstrates relatively low rates of reported perioperative adverse events in PCAS. Selective use of PCAS to treat carotid artery stenosis in those at highest risk for surgical complications is appropriate until the randomized trials of CEA vs PCAS provide concurrent short- and long-term outcome data.

Carotid endarterectomy for asymptomatic carotid stenosis

Carotid endarterectomy (CEA) is of proven benefit in recently-symptomatic patients with severe carotid stenosis. Its role in asymptomatic stenosis is still debated. The Asymptomatic Carotid Surgery Trial (ACST) more than doubled the number of patients randomised to CEA trials. This revised review incorporates the recently published ACST results. Our objective was to determine the effects of CEA for patients with asymptomatic carotid stenosis. We searched the Cochrane Stroke Group Trials Register (searched May 2004), MEDLINE (1966 to May 2004), EMBASE (1980 to June 2004), Current Contents (1995 to January 1997), and reference lists of relevant articles. We contacted researchers in the field to identify additional published and unpublished studies. All completed randomised trials comparing CEA to medical treatment in patients with asymptomatic carotid stenosis. Two reviewers extracted data and assessed trial quality. Attempts were made to contact investigators to obtain missing information. Three trials with a total of 5223 patients were included. In these trials, the overall net excess of operation-related perioperative stroke or death was 2.9%. For the primary outcome of perioperative stroke or death or any subsequent stroke, patients undergoing CEA fared better than those treated medically (relative risk (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83). Similarly, for the outcome of perioperative stroke or death or subsequent ipsilateral stroke, there was benefit for the surgical group (RR 0.71, 95% CI 0.55 to 0.90). For the outcome of any stroke or death, there was a non-significant trend towards fewer events in the surgical group (RR 0.92, 95% CI 0.83 to 1.02). Subgroup analyses were performed for the outcome of perioperative stroke or death or subsequent carotid stroke. CEA appeared more beneficial in men than in women and more beneficial in younger patients than in older patients although the data for age effect were inconclusive. There was no statistically significant difference between the treatment effect estimates in patients with different grades of stenosis but the data were insufficient. Despite about a 3% perioperative stroke or death rate, CEA for asymptomatic carotid stenosis reduces the risk of ipsilateral stroke, and any stroke, by approximately 30% over three years. However, the absolute risk reduction is small (approximately 1% per annum over the first few years of follow up in the two largest and most recent trials) but it could be higher with longer follow up.

High-Risk Carotid Endarterectomy

"High-risk" carotid endarterectomy (CEA): fact or fiction? To answer this question we reviewed the available evidence starting from controlled randomized trials, through retrospective population- and large institution-based studies to case-series. CEA can be performed in most "high-risk" patients with low mortality and morbidity. A broad concept of high-risk CEA, based merely on exclusion from previous controlled randomized CEA trials, cannot be justified. The vast majority of evidence suggests that age (> or =80 years) per se should not be considered a high-risk criterion for CEA. However, it appears that there are certain individual risk factors, which may influence outcome adversely. It appears that CEA in the setting of contralateral carotid occlusion may be associated with very slightly increased risk of adverse perioperative events. Local risk factors, namely carotid reoperation and CEA following prior cervical radiation therapy, are associated with slightly increased stroke, death and probably cranial nerve injury rates. If these risk factors are frequent in a particular series the overall outcome of CEA will be worse. In the absence of level-one evidence on the long-term efficacy of carotid artery stenting (CAS) in stroke prophylaxis, selection for CAS should be restricted to well-defined high-risk categories, such as severe medical comorbidities or local-anatomic risk factors.

A multicenter prospective analysis of 14,000 carotid endarterectomies

Abstract Introduction: The National Surgical Quality Improvement Program (NSQIP) is a prospectively gathered risk-adjusted database which randomly samples data from the Veterans Affairs (VA) health system, and 14 participating private hospitals. Utilizing the NSQIP database, this study was undertaken to identify the incidence of morbidity and mortality in the contemporary surgical practice of carotid endarterectomy (CEA). Methods: NSQIP data were examined for all patients under going CEA as a primary operation during the 2000–2003 period. This database captures over 150 variables utilizing trained nurse reviewers. Multivariate analysis was undertaken to identify variables associated with a composite of 30-day mortality, stroke or cardiac event. Results: 13,811 patients comprised the study population, 95% were male and 91% were from the VA sector. The average age was 68.5 ± 0.1 years, and 57.9% of the patients were symptomatic. The overall mortality, stroke and cardiac event rates were 2.1%, 1.7% and 1.1% respectively, giving a composite outcome of 4.0%. The combined stroke and death rate was 3.4%. The following variables impacted the composite outcome: age, pack-years of smoking, renal insufficiency, diabetes, previous stroke, history of TIA, hypoalbuminemia and ASA class. Conclusions: The NSQIP database provides a powerful tool to examine the outcome of CEA in current surgical practice. Identification of variables portending a poor outcome may be helpful in selecting patients for non-surgical interventional therapies. Given that the majority of the patients in this study were symptomatic, the results compare favorably to the randomized CEA trials.

Evaluation and Management of Asymptomatic Carotid Artery Stenosis

Internal carotid artery stenosis (ICAS) is responsible for approximately 30% of ischemic strokes. Internal carotid artery stenosis of greater than 50% is present in about 4% to 8% of the population aged 50 to 79 years. Natural history studies and clinical trials have shown a small increase in stroke risk in patients with increasing degrees of ICAS, especially in those with greater than 80% reduction in carotid artery diameter. Randomized, prospective multicenter trials have revealed the superiority of carotid endarterectomy (CEA) over medical therapy in recently symptomatic patients with severe ICAS. However, the evidence from several randomized controlled trials of CEA in asymptomatic patients does not support the use of CEA in most of these patients; also, the role of noninvasive screening in this patient population remains uncertain and controversial. Furthermore, there is considerable uncertainty about whether the statistical benefit of avoiding a nondisabling stroke is worth the overall cost and risk of the procedure. Clinicians continue to struggle with treatment decisions for patients with asymptomatic ICAS. Carotid endarterectomy for asymptomatic ICAS should be considered only for medically stable patients with 80% or greater stenosis who are expected to live at least 5 years, and only in centers with surgeons who have a demonstrated low (<3%) perioperative complication rate. We outline the prevalence and natural history of ICAS, the evidence for CEA in patients with asymptomatic ICAS, the roles of screening and monitoring for ICAS, the methods of evaluating ICAS, and the implications for practicing clinicians.

Long-term durability of carotid endarterectomy for symptomatic stenosis and risk factors for late postoperative stroke.

Carotid endarterectomy (CEA) reduces the risk of stroke ipsilateral to recently symptomatic severe carotid stenosis. Other techniques such as percutaneous transluminal angioplasty with stenting are currently being compared with CEA. Thus far, case series and several small, randomized, controlled trials of CEA versus percutaneous transluminal angioplasty (with and without stenting) have focused primarily on the 30-day procedural risks of stroke and death. However, long-term durability is also important. To determine the long-term risk of stroke after CEA and to identify risk factors, we studied patients in the European Carotid Study Trial (ECST), the largest published cohort with long-term follow-up by physicians after CEA. Risks of ipsilateral carotid territory ischemic stroke were calculated by Kaplan-Meier analysis starting on the 30th day after CEA in 1728 patients who underwent trial surgery. Risk factors were determined by Cox regression. For comparison, we also determined the "background" risk of stroke on medical treatment in the ECST in the territory of 558 previously asymptomatic contralateral carotid arteries with <30% angiographic stenosis (ECST method) at randomization. The risks of disabling ipsilateral ischemic stroke and any ipsilateral ischemic stroke were constant after CEA, reaching 4.4% [95% confidence interval (CI), 3.0 to 5.8] and 9.7% (95% CI, 7.6 to 11.7), respectively, by 10 years. The equivalent ischemic stroke risks distal to contralateral <30% asymptomatic carotid stenoses were 1.9% (95% CI, 0.8 to 3.2) and 4.5% (95% CI, 1.5 to 7.4). Presentation with cerebral symptoms, diabetes, elevated systolic blood pressure, smoking, male sex, increasing age, and a lesser severity of preoperative stenosis were associated with an increased risk of late stroke after CEA, but plaque morphology and patch grafting were not. Although the risk of late ipsilateral ischemic stroke after CEA for symptomatic stenosis is approximately double the background risk in the territory of <30% asymptomatic stenosis, it is still only approximately 1% per year and remains low for at least 10 years after CEA. This is the standard against which alternative treatments should be judged. Several risk factors may be useful in identifying patients at particularly high risk of late postoperative stroke.

The 27th International Stroke Conference San Antonio, Texas, February 7-9, 2002.

The 27th International Stroke Conference San Antonio, Texas, February 7-9, 2002.

Relation between prepublication release of clinical trial results and the practice of carotid endarterectomy.

Little is known about how clinical practice is affected by disseminating results of clinical trials prior to publication in peer-reviewed journals. To determine whether prepublication release of carotid endarterectomy (CEA) trial results via National Institutes of Health Clinical Alerts was associated with prompt changes in patient care that were consistent with the new medical evidence. Longitudinal data series analysis using acute care hospital discharge data from the Healthcare Cost and Utilization Project for patients who had CEA performed in acute care hospitals in 7 states (New York, California, Pennsylvania, Florida, Colorado, Illinois, and Wisconsin). The trials were the North American Symptomatic Carotid Endarterectomy Trial (NASCET clinical alert released February 1991) and the Asymptomatic Carotid Atherosclerosis Study (ACAS clinical alert released September 1994). Carotid endarterectomy rate during each month from 1989 (2 years before the NASCET clinical alert) to 1996 (2 years after the ACAS clinical alert), adjusted for age and sex. Because both trials were limited to patients 80 years or younger in hospitals with low mortality, we also stratified CEA rates by patient age and hospital mortality rate. From 1989 through 1996, 272849 CEAs were performed in the acute care hospitals in these 7 states, with the annual number increasing from 22300 to 51 495. Afterthe NASCET clinical alert, the adjusted CEA rate increased 3.4% per month (95% confidence interval [CI], 1.6%-5.3%) during the following 6 months and then increased 0.5% per month (95% CI, 0.2%-0.8%; P<.04) after journal publication of the NASCET study. After the ACAS clinical alert, the CEA rate increased 7.3 % per month (95% CI, 6.0%-8.5%) during the following 7 months and then decreased by 0.44% per month (95% CI, -0.86% to -0.0002%; P<.04) after journal publication of the ACAS study. After the ACAS clinical alert, the CEA rate increased more in patients aged 80 years or older than in younger patients; whereas, after journal publication of ACAS, the CEA rate decreased more rapidly in the older population. The overall proportion of CEAs performed in low-mortality hospitals did not change substantially after release of the clinical alerts or after journal publication. In this study, prepublication dissemination of CEA trial results with clinical alerts was associated with prompt and substantial changes in medical practice, but the observed changes suggest that the results were extrapolated to patients and settings not directly supported by the trials.

Status report on the carotid revascularization endarterectomy versus stent trial

Carotid angioplasty and stenting (CAS) is a relatively new procedure that has been used increasingly in recent years. Its growth is caused, at least in part, by the perceived advantages of a less invasive treatment for extracranial carotid occlusive disease. However, data comparing the efficacy of CAS with carotid endarterectomy (CEA), which is the gold standard for treatment of symptomatic carotid stenosis, are not available. The Carotid Revascularization Endarterectomy versus Stent Trial (CREST) will compare the relative efficacy of CAS with CEA in preventing stroke, myocardial infarction, and death during a 30-day periprocedural period. The efficacy of the 2 procedures in preventing ipsilateral stroke over a follow-up period of up to 4 years will also be assessed. Cerebrovascular events will be verified by an Adjudication Committee masked to the assigned treatment. Secondary outcomes assessment will include the following: (1) differential efficacy of CAS and CEA in men and women, (2) comparison of periprocedural (30-day) morbidity with late postprocedural (after 30-days) morbidity and mortality that is associated with the procedures, (3) estimation and comparison of the restenosis rates associated with the 2 procedures, (4) evaluation of differences in measures of health-related quality of life and cost effectiveness, and (5) identification of subgroups of participants at differential risk for CAS and CEA. The primary eligibility criteria are a significant (greater than 50% as shown by cerebral angiography) stenosis of the carotid artery in a patient with amaurosis fugax (transient monocular blindness), transient ischemic attack, or ipsilateral nondisabling stroke. Men and women will be eligible for the trial, but patients with medical conditions that are likely to limit their participation during the follow-up or to interfere with outcome evaluation will be excluded. After a credentialing and training phase, 2,500 patients will be randomized to the treatment groups. Statistical analysis of the primary outcome will use standard survival methodology.

Antiplatelet therapy in secondary stroke prevention.

This article focuses on recent data about the safety and effectiveness of antiplatelet therapies for secondary stroke prevention. Highlights include a discussion of changes in the professional labeling for aspirin and the results of a low- versus high-dose aspirin trial (Aspirin after Carotid Endarterectomy trial). Safety issues regarding aspirin also are considered. Other topics include a review of recent data on thrombotic thrombocytopenic purpura (TTP) associated with ticlopidine and a brief update on clopidogrel. A summary of discussions related to the European Stroke Prevention Study 2 data and Food and Drug Administration consideration of combination dipyridamole/aspirin therapy are presented.

Reconstructive surgery of the extracranial arteries.

The first carotid endarterectomy (CEA) is usually accredited to Eastcott who reported in 1954 the successful incision of a diseased carotid bulb with end-to-end anastomosis of the internal carotid artery (ICA) to the common carotid artery (CCA). During the following years surgeons were quick to adopt and improve the intuitively attractive procedure. But by the early to mid 1980s several leading neurologists began to question the growing number of CEAs performed at that time. Six major CEA trials were then designed which are now completed or nearing completion. Most conclusive data are available from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) for symptomatic carotid disease, and from the Asymptomatic Carotid Atherosclerosis Study (ACAS) for asymptomatic carotid disease. The key result of these studies is that CEA is beneficial to high grade symptomatic and asymptomatic carotid stenosis. While the benefit in symptomatic disease is clear, it may be negligible in asymptomatic patients suffering from other medical conditions, the most important being coronary artery disease. Since the conclusions from the different studies vary significantly, guidelines and recommendations with regard to CEA have been issued by a number of interest groups, so-called consensus conferences. The best known guidelines are published by the American Heart Association (AHA). However, the practice of interest groups to issue guidelines is currently being criticized, the main reason being that interest groups have different ideas and all claim the right to issue guidelines. At present we recommend CEA for symptomatic high-grade stenosis in patients without significant coincident disease. With regard to asymptomatic stenosis we suggest surgery to otherwise healthy patients if the stenosis is very narrow or progressive. Preoperative evaluation has changed over the years. Currently we recommend duplex sonography in combination with intra- and extracranial magnetic resonance angiography (MRA). Concurrent coronary artery disease is a major consideration in the perioperative management, and the use of a specific algorithm is recommended. Surgery is performed under general anaesthesia with intraoperative monitoring such as electroencephalography (EEG) and transcranial Doppler (TCD). A temporary intraluminal shunt is used selectively if after cross-clamping the flow velocity in the middle cerebral artery (MCA) falls to below 30 to 40% of baseline. For years we employed routine barbiturate neuroprotection during cross-clamping. At the present time we use barbiturate selectively, if the flow velocity in the MCA falls to below 30 to 40% of baseline and if the use of a temporary intraluminal shunt is not possible due to difficult anatomic conditions. The reason to abandon systematic barbiturate protection was to accelerate recovery from anaesthesia. Our patients are monitored overnight on the ICU or a surveillance unit. Routine hospitalization after surgery is 5 to 7 days with a control duplex sonography being performed prior to discharge. A number of details with regard to surgical technique and perioperative management are a matter of discussion. Our surgical routine is described here step by step. Such management resulted in 6 major complications among the 402 cases with 4 of cardiopulmonary and 2 of cerebrovascular origin. For the future we can expect the development of percutaneous transluminal techniques competing with standard carotid endarterectomy. At the present time several comparative studies are under way. Irrespective of the technical approach to treat carotid stenosis, several other issues have to be clarified before long. One of the major unresolved items is the timing of treatment after completed stroke. In this regard prospective trials need to be performed. Although numerically not as important as carotid stenosis, vertebral artery (VA) and subclavian artery (SA) stenoses are more and more accepted as indication for surgical

Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial

Background: Carotid angioplasty (CA) has been suggested to be a safer and more costeffective alternative to carotid endarterectomy (CEA) in the management of symptomatic severe internal carotid artery (ICA) disease. Methods: The study was conducted as a prospective consecutive randomised trial of CEA versus CA for symptomatic severe ICA disease in a university teaching hospital. All patients were assessed before and after surgery by a neurologist. The study consisted of 23 patients with focal carotid territory symptoms and severe ICA stenosis (> 70%) who were randomized to either CEA or CA. However, only 17 had received their allocated treatment before trial suspension. CEA with patching or CA with stenting were used as interventions. The main outcome measures were death or disabling or nondisabling stroke within 30 days. Results: All 10 CEA operations proceeded without complication, but 5 of the 7 patients who underwent CA had a stroke ( P=0.0034), 3 of which were disabling at 30 days. Conclusions: After referral, the Data Monitoring Committee subsequently concluded that the trial was suspended. The investigators and the Ethics Committee subsequently concluded that the trial could not be restarted - even in an amended format - primarily because of problems with informed consent. We review many of the ethical dilemmas encountered in the performance of this study. If future trials do suggest a selected role for CA, it is essential that both the inclusion and the exclusion criteria are fully documented.