Mateen F. Abidi, MD,<sup>1</sup> Nicolai Mejevoi, MD,1 Marc Cohen, MD,<sup>1,2</sup> Bruce Brener, MD,<sup>1</sup> Najam Wasty, MD, FACC<sup>1</sup>
The authors also acknowledge Gail Baker, APN,<sup>1</sup> for her efforts and contributions to the research.
Background. Carotid artery stenting (CAS) is evolving as a less invasive alternative to carotid endarterectomy (CEA) to treat patients with carotid artery stenosis at high surgical risk. However, little is known about the quality and safety of CAS in a relatively low volume, community hospital setting, especially when used as an alternative to CEA for high-risk surgical candidates. Objective. To analyze outcomes of CAS performed in a low-volume community hospital setting. Methods. This was a retrospective, observational study of outcomes in 81 consecutive high surgical risk patients treated with self-expandable carotid stent system with embolic protection device in Newark Beth Israel Medical Center (NBIMC) from March 2004 to December 2008. The endpoints were: procedural success; 30-day composite rate of stroke, death or myocardial infarction (MI); 1-year composite rate of ipsilateral stroke, death or MI; 1-year rate of restenosis. Results. Procedural success was achieved in 98% of the entire cohort. Composite 30-day incidence of stroke, death or MI occurred in 7.4% of patients, primarily due to stroke (4.9%) with statistically significant (20% vs 3.3%, p=0.03) decrease in the occurrence of adverse events as compared in the very first 20 patients (group 1) and the subsequent 61 patients (group 2) to demonstrate a “learning curve” phenomenon. Conclusions. CAS is an effective procedure with high procedural success in the setting of a relatively small volume center. The overall adverse event rate after CAS was comparable to data presented in published CAS trials and registries. After a clear-cut “learning curve,” extending beyond experience required by present credentialing process, the results were dramatically improved and competitive.
VASCULAR DISEASE MANAGEMENT 2011;8:E126–E131
Carotid artery stenting (CAS) as an alternative to carotid endarterectomy (CEA) evolved and peaked following publication of the results of Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial.1 The SAPPHIRE trial favored CAS with distal embolic protection compared to CEA in high-risk patients with severe carotid stenosis and coexisting medical conditions. CAS then expanded to off-label use in patients with average surgical risk. However, this trend significantly slowed after publication of the results of 2 European trials, EVA-3S2 and SPACE,3 which failed to demonstrate non-inferiority of CAS compared to CEA in patients with low to average surgical risk.
Pending the results from the American-based Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), and the International Carotid Stenting Study (ICSS) comparing CAS and CEA in patients with average surgical risk, and because there is a substantial group of high-risk patients, who either refuse CEA or are turned down for CEA by vascular surgeons, our institution decided to pursue a protocol-based CAS team approach. The purpose of our study was to analyze outcomes of CAS performed by a team of an interventional cardiologist and a vascular surgeon in real-world, high-risk surgical patients, treated in a community hospital with a high volume of coronary and non-carotid peripheral interventions.
This was a retrospective observational study of outcomes in consecutive high-risk surgical carotid artery stenosis patients (SAPPHIRE criteria) treated with self-expanding carotid stent system and distal embolic protection device at our institution from March 2004 to December 2008. Eligible patients with carotid artery disease met general FDA recommendations of high surgical risk based on specific anatomic and comorbid clinical criteria (Table 1), and were considered for CAS by both a very experienced vascular surgeon and an interventional cardiologist. Our institutional review board approved the study.
Early CAS procedures were performed by 2 operators (1 interventional cardiologist as primary operator with a credentialed vascular surgeon as a secondary operator), both credentialed according to an existing protocol after performing the required number of supervised interventions: both operators had more than 15 years of experience in non-carotid peripheral interventions, including supra-arch interventions. Each operator performed more than 50 cerebral angiograms and more than 10 carotid stenting procedures prior to starting the program in our hospital. Each was credentialed according to in-hospital protocol in accordance with the American College of Cardiology (ACC), the American College of Physicians (ACP), the Society for Cardiovascular Angiography and Interventions (SCAI), the Society for Vascular Medicine and Biology (SVMB), and the Society for Vascular Surgery (SVS) clinical competence statement.4
All patients were pretreated with aspirin 325 mg and clopidogrel 300 mg, unless they were already on both medications. All patients received intraprocedural heparin to maintain an activated clotting time of 250 to 300 seconds. Frequent neurological examinations were performed during the procedures. Aspirin was continued indefinitely, while clopidogrel was stopped after 1 month, unless patients had other indications for dual antiplatelet therapy.
The degree of common carotid artery, bifurcation, or internal carotid artery (ICA) stenosis was assessed first by ultrasound and reexamined by angiography in symptomatic and asymptomatic patients as determined by the operator (visual estimate) per the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria.5
The stent used was a self-expanding, nitinol stent with distal embolic protection device: Carotid WALLSTENT® plus FilterWire EX®/EZ™ Embolic Protection System (Boston Scientific, Natick, Massachusetts) in 4 patients and Carotid RX Acculink™/Accunet™ system (Abbott Vascular, Abbott Park, Illinois) in 77 patients.
Endpoints Assessed. The following endpoints were assessed in all 81 patients:
- Procedural success, lesion dilatation and stent placement, achieving less than 30% residual diameter stenosis without immediate clinical or angiographic complications.
- 30-day composite rate of stroke, death or MI.
- 1-year composite rate of ipsilateral stroke, death or MI.
- 1-year rate of carotid restenosis (more than 50% by ultrasound or angiography).
Outcomes were further stratified by groups to assess a possible effect of the learning curve: group 1 consisted of the first 20 patients (10 by each operator); group 2 consisted of the subsequent 61 patients. We made a “cut-off” at 10 patients per operator, considering results of CREST trial lead-in phase, recommending a minimum of 10 procedures performed by the operator to be credentialed for the inclusion into the trial.6
During the follow-up period, all patients had a carotid duplex ultrasound and neurological exam, which was performed by an advanced practitioner nurse (APN). This APN worked for the primary interventional cardiologist and if the APN detected a change in neurological exam or neurological deficit, then a complete neurology consult was called. All patients had an assessment for clinical events at 1 month, 6 months and 12 months, according to office notes.
Statistics. Results were analyzed using standard statistical methods, including: Fisher’s exact test, χ2 with Yates’ correction test and t- test. Statistical significance was set at anαα level of 0.05, 2-tailed p-values were used. SAS package was used for statistical analysis. Data were presented by: all patients; group 1: first 20 patients; and group 2: subsequent 61 patients.
Patient Characteristics (Table 1). Patients’ mean age was 71.2 ± 8.6 years. More than 40% of the patients had retinal or hemispheric symptoms prior to index CAS procedure. About one third of the patients had an occluded contralateral carotid artery, 12% of patients had previous ipsilateral CEA, and 35% of patients had 2- or 3-vessel CAD or left main CAD in need of coronary artery bypass surgery. Thirty percent of the patients had class III/IV congestive heart failure or severe left ventricular systolic dysfunction. There was no statistically significant difference between the groups.
Procedural success was achieved in 98% of the entire cohort, and in 100% of patients in group 2 (Table 2). Periprocedural complications, as assessed by composite 30-day incidence of stroke, death or MI occurred in 7.4% of patients, primarily due to stroke (4.9%) with statistically significant (20% vs 3.3%, p=0.03) decrease in the occurrence of adverse events in group 2. There was only 1 death overall during the 30-day period in group 2 related to immediate outcome of the CABG surgery for severe left main disease 2 weeks post CAS procedure.
One-year rate of the composite of ipsilateral stroke, death or MI was 8.6% with a statistically significant difference between the groups (25% vs 3.3%, p=0.009) and higher incidence of adverse outcomes in group 1 (first 20 patients). There was no statistically significant difference between the 2 groups in a 1-year rate of restenosis.
Stroke is the third leading cause of death, and is the leading cause of serious long-term disability in the United States, with CAD amenable to revascularization accounting for 5% to 12% of new strokes. Concurrently, progression of carotid atherosclerosis is difficult to predict, and about 80% of strokes due to embolization in the carotid distribution occur as a primary event.7 Thus, careful evaluation and follow-up of the patients with carotid artery disease is needed.
Several options are available to treat patients with carotid artery disease, including medical therapy alone, or combined with revascularization, which is achieved by surgery (CEA) or endovascular intervention (CAS).
When studying the value of CAS in primary and secondary stroke prevention, it is important to first remember that studies documenting the benefit of carotid intervention were conducted before the widespread use of aggressive medical treatment such as clopidogrel, extended-release dipyridamole and aspirin, statins, smoking cessation and aggressive blood pressure control. Also, medical therapy may be the only option in some selected very high-risk patients.
Multiple studies evaluated efficacy of different pharmacological approaches in the stroke prevention. Daily aspirin therapy (75–325mg) results in a 25% relative risk reduction of stroke.8,9 The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial demonstrated a statistically significant benefit of clopidogrel for the combined endpoint of ischemic stroke, MI, or vascular death compared with aspirin.10 The Management of Atherothrombosis with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial showed that clopidogrel alone was as good as aspirin and clopidogrel for secondary stroke prevention with increased bleeding risk of the combination therapy.11 Despite isolated data from a single trial regarding secondary prevention, the preponderance of evidence is that the addition of extended-release dipyridamole to aspirin alone for primary or secondary stroke prevention is of marginal benefit.8,9,12,13 Several large studies have demonstrated stroke reduction with the use of statins.14 Both the Scandinavian Simvastatin Survival Study (4S) trial15 and the Cholesterol and Recurrent Events (CARE) trial16 with pravastatin demonstrated a 30% relative risk reduction for stroke compared with placebo. Interestingly, the stroke benefit did not appear in these trials until after 3 years of therapy. In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of stroke.17 Also, lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke, but not stroke severity or disability.18 Therefore, optimization of medical therapy is a very important part of the management of patients with carotid stenosis.
Much remains to be done to identify patients at particularly high risk of ipsilateral stroke, for whom carotid intervention either CAS or CEA is necessary in addition to medical therapy. Efficacy of CEA in addition to aspirin compared to aspirin alone for stroke prevention was shown in several studies in the early 1990s,5,19 and current American Heart Association (AHA) guidelines recommend CEA for symptomatic patients with carotid artery stenosis of 50% to 99%, if estimated perioperative risk of stroke or death is less than 6%, or less than 3% for patients with asymptomatic 60% to 99% carotid stenosis.20
The SAPPHIRE trial1 favored CAS with distal embolic protection compared to CEA in high-risk patients with severe carotid stenosis and coexisting medical conditions. CAS then expanded to off-label use in patients with average surgical risk. However, this trend has significantly slowed after publication of the results from EVA-3S2 and SPACE,3 which failed to demonstrate non-inferiority of CAS compared to CEA in patients with low to average surgical risk. With the rapid evolution of catheter-based techniques for carotid revascularization, stenting has become feasible in a wide spectrum of patients, but appropriate case selection, particularly in the treatment of asymptomatic patients and operator experience are the major determinants of the risk-benefit ratio of carotid stenting.
The goal of this retrospective analysis was to find out whether CAS is an effective and safe strategy, when performed in a relatively low-volume setting in a hospital, which has a high volume of coronary and non-carotid peripheral interventions and experienced peripheral operators.
As presented above, rate of perioperative complications in our study was slightly higher than expected, when compared to previously published data, including SAPPHIRE trial1 and Carotid Acculink/Accunet Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE) registry.21 Also, an estimated risk of complications as per CEA guidelines—3% in asymptomatic and 6% for symptomatic patients—was exceeded.
Several factors influencing the outcomes in our study should be considered including: patient-related factors (age, presence of the symptoms related to carotid artery disease, and comorbidities, carotid and aortic arch anatomy); procedure-related factors, including effectiveness and experience of the operators (performance of lesion predilatation, number of dilatations, timing and positioning of embolic protection device).
We analyzed our outcomes compared to the SAPPHIRE trial, the only randomized trial analyzing outcomes in high surgical risk patients, both symptomatic and asymptomatic, and CAPTURE registry, which included a similar group of patients and also utilized the Acculink™/Accunet™ stent/embolic protection device system (Abbott Vascular). The same equipment was used in the majority of our patients.
The composite endpoint of 30-day rate of stroke, death or MI in CAPTURE registry was 6.3%, and 4.8% in the stent arm of the SAPPHIRE trial (Table 3).
Mean age of the patients in our cohort was 71.2 years, which is slightly less than the 72.7 and 72.5 years in CAPTURE registry and SAPPHIRE trial, respectively. Forty-two percent of patients in our cohort had symptomatic carotid stenosis compared to 29% in SAPPHIRE and only 13.8% in CAPTURE registry. It is possible that our slightly worse outcomes compared with SAPPHIRE and CAPTURE stent cohorts could be attributed to a relatively higher number of symptomatic patients. For example, the CAPTURE registry odds ratio for primary endpoint was 2.5 by multivariate analysis in symptomatic patients.21 In fact, cumulative adverse periprocedural outcomes in our symptomatic patients occurred in 8.8% of cases, compared with 12% in real-life CAPTURE registry and remarkably low 2.1% (compared to 5.4% in asymptomatic subgroup) in SAPPHIRE trial (Table 3).
However, we found the most striking differences when we analyzed the dynamics of outcomes in our cohort (Figure 1). We chose to assess separately the outcomes in the first 20 procedures (10 per each primary operator), followed by the rest of our patients. The reason to choose 10 patients per operator was that this is a minimal number of independent procedures required to start enrolling for CAS arm in the CREST trial.6 We observed a dramatic, statistically significant decrease (from 20% to 3.3%) in the occurrence of 30-day stroke/death/MI in patients undergoing CAS in our hospital. Improvements were achieved in both symptomatic and asymptomatic subgroups with the rate of 30-day death or stroke well below established margin of 6% and 3% respectively (Table 3). These differences in adverse outcomes were maintained at 1-year follow-up.
The evolution of outcomes as observed in our cohort is critical to the understanding of the results of the EVA-3S study,2 where a significant amount of low-initial-experience operators were involved and 9.6% 30-day rate of stroke and death was reported in CAS group. Both of our primary operators fulfilled all requirements for pre-approval experience in cerebral angiography and number of supervised procedures.
Verzini et al reported his analysis of CAS outcomes in a high-volume vascular center and suggested insufficient learning experience, which is usually required for credentialing.22 Interestingly, the CAPTURE registry has not revealed differences in adverse outcomes on the basis of operator experience, although there was a trend towards better outcomes with high volume operators. It appears that beginning the CAS interventions, and growing experience, rather than just high volume of interventions influences the outcomes. In addition, Roffi et al reported extremely low 30-day rate of death, stroke or MI in his cohort (1.9%), after starting a hospital CAS program, following completion of CAS fellowship.23 Also, Friedel et al reported remarkably excellent short-term (1 stroke/death – 2% at 30 days) and long-term results achieved in 44 patients undergoing CAS in low-volume settings in the community hospital.24 The extremely low complication rate showed there was no evident learning curve effect.
The learning curve generally levels out as experience increases, resulting in fewer complications and less of a need to convert to the standard procedure. This learning curve gives rise to many ethical and legal dilemmas especially in a low-volume setting. Treating a single unique patient may or may not entail greater risks than treating patients with common diseases, but the former will never constitute a learning curve. Participating in clinical research clearly limits the physician's autonomy and imposes additional ethical and legal obligations. To ensure the scientific integrity of the research, as well as the safety of patients, the physician-investigator is legally and ethically obligated to seek and accept professional oversight, concurrence and critical outcome analysis.
CAS is an effective procedure with high procedural success in the settings of relatively small volume center. The overall adverse event rate after CAS was comparable to published CAS trials and registries. After a clear-cut learning curve, extending beyond experience required by the present credentialing process, the results were dramatically improved and competitive.
- Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493–1501.
- Mas JL, Chatellier G, Beyssen B, et al. EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006;355:1660–1671.
- SPACE Collaborative Group, Ringleb PA, Allenberg J, Brückmann H, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: A randomised non-inferiority trial. Lancet 2006;368:1239–1247.
- ACC/ACP/SCAI/SVMB/SVS clinical competence statement on vascular medicine and catheter-based peripheral vascular interventions: A report of the American College of Cardiology/American Heart Association/American College of Physicians Task Force on Clinical Competence (ACC/ACP/SCAI/SVMB/SVS writing committee to develop a clinical competence statement on peripheral vascular disease). J Am Coll Cardiol 2004;44:941–957.
- North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–453.
- Hobson RW 2nd, Howard VJ, Roubin GS, et al. Credentialing of surgeons as interventionalists for carotid artery stenting: Experience from the lead-in phase of CREST. J Vasc Surg 2004;40:952–957.
- Inzitari D, Eliasziw M, Gates P, et al. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 2000;342:1693–1700.
- Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 2002;324:71–86.
- Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:483S–512S.
- A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329–1339.
- Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): Randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–337.
- Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: A double-blind, active and placebo-controlled study. Lancet Neurol 2008;7:875–884.
- Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1–13.
- Law MR,Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: Systematic review and meta-analysis. BMJ 2003;326:1407–1408.
- Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389.
- Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001–1009.
- The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006;355:613–615.
- Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567–1577.
- Randomised trial of endarterectomy for recently symptomatic carotid stenosis: Final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379–1387.
- Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy: A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation 1998;97:501–509.
- Gray WA, Yadav JS, Verta P, et al. The CAPTURE registry: Predictors of outcomes in carotid artery stenting with embolic protection for high surgical risk patients in the early post-approval setting. Catheter Cardiovasc Interv 2007;70:1025–1033.
- Verzini F, Cao P, De Rango P, et al. Appropriateness of learning curve for carotid artery stenting: An analysis of periprocedural complications. J Vasc Surg 2006;44:1205–1211.
- Roffi M, Greutmann M, Eberli FR, et al. Starting a carotid artery stenting program is safe. Catheter Cardiovasc Interv 2008;71:469–473.
- Friedell ML, Sandler BJ, Andriole JG, et al. Carotid angioplasty and stenting is a safe and durable procedure in a community hospital. Am Surg 2007;73:543-546; discussion 546–547.
From the 1Division of Cardiology, Newark Beth Israel Medical Center, Newark, New Jersey and 2Mount Sinai School of Medicine, New York, New York.
The authors report no financial relationships or conflicts of interest regarding the content herein.
Manuscript submitted March 10, 2011, provisional acceptance given April 28, 2011, final version accepted May 27, 2011.
Address for correspondence: Mateen F. Abidi, MD, Newark Beth Israel Medical Center, 201 Lyons Avenue, Newark, NJ 07112. Email: email@example.com