Regarding “Carotid artery stenting has increased rates of postprocedure stroke, death, and resource utilization than does carotid endarterectomy in the United States, 2005”

LETTERS TO THE EDITOR There is no sex equality in carotid disease In his commentary in the Journal of Vascular Surgery Abstract section on the article by Henriksson et al,1 which concluded that to all intents and purposes carotid endarterectomy (CEA) was not cost-effective in women with asymptomatic carotid disease, Dr Greg Moneta2 observed that although the data were interesting, it seemed “politically untenable to deny women, and not men, prophylactic CEA for high grade asymptomatic stenosis.” At first sight, this seems a not unreasonable observation, but it does require the reader to assume that women gain equivalent clinical benefit (in terms of long term stroke prevention) to men. In fact, this is not the case. In the original Asymptomatic Carotid Atherosclerosis Study (ACAS) publication,3 the authors conceded that CEA did not confer significant benefit in women, with an absolute risk reduction in ipsilateral stroke of 1.7% at 5 years. Even when all strokes and deaths occurring in the first 30 days were later excluded,4 there was still no significant benefit observed in women. ACST subsequently claimed that CEA conferred significant benefit in women,5 but this was only the case if the operative risk was excluded (ie, the 5-year benefits were modelled on a zero percent procedural risk). Once the procedural risk was included, all significant benefit in women ceased.6 When the ACAS and Asymptomatic Carotid Surgery Trial (ACST) data were combined, the Cochrane Collaboration7 performed a subgroup analysis in 1644 women and again noted that CEA did not significantly reduce the 5-year risk of stroke compared with best medical therapy (odds ratio, 0.96; 95% confidence interval, 0.63-1.45). The lower magnitude of benefit observed in women is almost certainly due to a combination of there being a slightly higher procedural risk compared with men (a consistent finding across all of the symptomatic and asymptomatic randomized trials and also in a systematic review of the published literature)8 combined with a lower late natural history risk of stroke compared with men. The article by Henriksson et al is undoubtedly a provocative way of demonstrating the reduced clinical benefit conferred by CEA in women, and Greg Moneta’s observation will be typical of many who are intuitively reluctant to treat men and women differently. More important, until the guideline makers address this issue, surgeons will remain reluctant to advise against offering CEA to women because of a very real fear of uncritical medicolegal censure. This, if nothing else, is another compelling reason for urging the principle investigators of trials comparing CEA with carotid stenting in asymptomatic patients to include a medical arm in the randomization process. Continuing to ignore this important clinical issue is also neither professionally nor politically tenable. Professor A. Ross Naylor, MD, FRCS Leicester Medical School Department of Cardiovascular Sciences Vascular Surgery Group Leicester LE2 7LX, United Kingdom REFERENCES 1. Henriksson M, Lundgren F, Carlsson P. Cost-effectiveness of endarterectomy in patients with asymptomatic carotid artery stenosis. Brit J Surg 2008;95:714-20. 2. Moneta G. Cost-effectiveness of endarterectomy in patients with asymptomatic carotid artery stenosis [abstract commentary of Henriksson M, Lundgren F, Carlsson P. Brit J Surg 2008;95:714-20]. J Vasc Surg 2008;48:769-70. 3. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-8.

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4. Young B, Moore WS, Robertson JT, Toole JF, Ernst CB, Cohen SN, et al. An analysis of peri-operative surgical mortality and morbidity in the Asymptomatic Carotid Atherosclerosis Study. Stroke 1996;27:2216-24. 5. Asymptomatic Carotid Surgery Trial Collaborators. The MRC Asymptomatic Carotid Surgery Trial (ACST): carotid endarterectomy prevents disabling and fatal carotid territory strokes. Lancet 2004;363:1491-502. 6. Rothwell PM. ACST: which subgroups will benefit most from carotid endarterectomy. Lancet 2004;364:1122-3. 7. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 2005;CD001923. 8. Bond R, Rerkasem K, Cuffe R, Rothwell PM. A systematic review of the associations between age and sex and the operative risks of carotid endarterectomy. Cerbrovasc Dis 2005;20:69-77. doi:10.1016/j.jvs.2008.10.071

Regarding “Carotid artery stenting has increased rates of postprocedure stroke, death, and resource utilization than does carotid endarterectomy in the United States, 2005” In December 2008, McPhee et al warned about the dangers of carotid artery stenting (CAS) in increasing risks of perioperative mortality (1.1% vs 0.57%, P ⫽ .04) and stroke (1.8% vs 1.1%, P ⬍ .05; odds ratio [OR] 1.7; 95% confidence interval [CI] 1.2-2.3) compared with carotid endarterectomy (CEA).1 The warnings, based on large U.S. coding datasets and published in The Journal of Vascular Surgery, immediately raised great resonance condemning CAS. Are these alerts completely justified? At this point we do not know, since the numbers and the data are not as powerful as the conclusive words to prove increased mortality and stroke risks. According to multivariate analysis in the McPhee paper, the only strong predictors of perioperative mortality were renal failure (OR 2.7; 95% CI 1.6-4.6, P ⫽ .0004) and congestive heart failure (CHF) (OR 2.8; 95% CI 1.7-4.5, P ⬍ .0001), these being the same two baseline factors significantly more frequent in the CAS vs CEA group (3.9% vs 3%, P ⫽ .02 and 11.4% vs 6.8%, P ⬍ .0001, for renal failure and CHF in CAS and CEA, respectively). The higher mortality in CAS patients could be due to the procedure itself or more realistically, the high fatality rate was biased by baseline unbalance and a higher proportion of patients with high fatality risk factors at baseline. Even if CAS finally passes in the future, the procedure will never be for all practitioners. It is required that CAS be performed exclusively in centers with specific dedicated experience and adequate training. Large beds and teaching hospitals may be enough to provide high medical and surgical standards of care but may not be enough to ensure safe proficiency with new procedures as CAS. In the McPhee et al dataset, CAS population was about 10% of the overall population (90% being CEAs), suggesting that CAS centers were not actively working and were without large carotid experience. It would be interesting if the Authors could provide the number of CAS procedures per center (or better, the number of CAS per operators, if data are available) to provide data on experience and include this in a multivariate analysis on outcome. With a track record of less than 50 CAS, it is not recommended to perform CAS.2,3 Are CAS and CEA populations, as detected by the coding datasets, truly representative of the U.S. reality? It is quite unusual that 90% of CEA were performed in asymptomatic patients and almost half of the population was female (in other series, females were about 30% and asymptomatics about 60%).4 These are two subgroups (asymptomatic and female) of patients for whom treatment of carotid stenosis has been proven to be of lesser benefit, particularly in U.S. carotid trials (Asymptomatic Carotid Athero-

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sclerosis Study [ACAS], North American Symptomatic Carotid Endarterectomy Trial [NASCET]). Incomplete coded data, unrepresentative of the real world, selection bias, and type ␤ errors should be taken into account before spreading alarm. At this time, the available data are not mature enough to prove or disprove CAS. We should have an open mind while waiting for the truth to come to light together with more robust numbers (from randomized clinical trial (RCT) as the final data of Carotid Revascularization Endarterectomy Versus Stenting Trial [CREST]) before prematurely condemning the still young but promising CAS procedure. Paola De Rango, MD Gianbattista Parlani, MD Piergiorgio Cao, MD, FRCS Division of Vascular and Endovascular Surgery University of Perugia Hospital S.M. Misericordia 06100 Perugia, Italy REFERENCES 1. McPhee JT, Schanzer A, Messina LM, Eslami MH. Carotid artery stenting has increased rates of postprocedure stroke, death, and resource utilization than does carotid endarterectomy in the United States, 2005. J Vasc Surg 2008;48:1442-50. 2. Cremonesi A, Setacci C, Bignamini A, Bolognese L, Briganti F, Di Sciascio G, et al. Carotid artery stenting: first consensus document of the ICCS-SPREAD Joint Committee. Stroke 2006;37:2400-9. 3. Verzini F, Cao P, De Rango P, Parlani G, Maselli A, Romano L, et al. Appropriateness of learning curve for carotid artery stenting: an analysis of periprocedural complications. J Vasc Surg 2006;44:1205-11. 4. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 2008;7:915-26. doi:10.1016/j.jvs.2009.02.214

Reply This letter is written in response to the author(s) of the letter to the editor in which concerns are expressed about our recent publication in The Journal of Vascular Surgery entitled “Carotid artery stenting has increased rates of post-procedure stroke, death, and resource utilization than does carotid endarterectomy in the United States, 2005.”1 We certainly appreciate their careful review of our work and would like to address several points raised by the authors. In the letter to the editor, the author states that, “we should have an open mind while waiting for the truth to come to light with more robust numbers before prematurely condemning the still young but promising CAS procedure.” Like most practitioners we too are anxiously awaiting the definitive results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) trial to help shape our practice patterns and we would like to clarify that our population-based study from the Nationwide Inpatient Sample (NIS) in 2005 was not meant to “condemn” carotid artery stenting (CAS). Rather, our purpose was to provide the most up-to-date, and dispassionate review of the nationwide experience on post-procedure outcomes for the treatment of carotid artery stenosis during a year (2005), in which a dedicated International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9CM) code existed for CAS. In fact, in comparing our 2008 work with our previously published data from previous years,2 we state in the penultimate paragraph of this article, “Of interest, it seems that over time, the outcomes for CAS may be improving, and the current work shows that by 2005 the previously large gap between carotid endarterectomy (CEA) and CAS may be narrowing.”1

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The letter writer is rightfully concerned about the fact that “the higher mortality in CAS patients could be due to the procedure itself or more realistically, the high fatality rate biased by baseline unbalance and a higher proportion of patients with high fatality risk factors at baseline.” We are in agreement, which is why we went to great lengths in the discussion to address this likely unmeasured selection bias from administrative datasets, “We have attempted to account for certain patient co-morbid medical conditions using validated software, however, this is limited information and does not speak to the severity of a patient’s disease state, which would represent a selection bias whereby the sickest and highest risk patients likely underwent CAS”1 and “It is important to recognize that the observations made in this work regarding mortality, post-procedure stroke and resource utilization related to CEA and CAS are likely multi-factorial. We are unable to determine to what extent a patient’s mortality, morbidity, length of stay (LOS), or hospital charge is directly attributable to the procedure itself or whether it was related to a pre-existing co-morbidity or other mitigating factor.”1 We would also agree with the letter writer that, despite our best efforts, we have not accounted for individual CAS providervolume as this information is simply unobtainable from this type of dataset. We further mention that our observations are “within the limitations of a large administrative dataset, which include a lack of comprehensive risk stratification by procedure type.”1 Despite the expressed shortcomings of using administrative databases, shortcomings that are extensively described in our paper,1 we would like to point out to the authors that we are not an outlier in our observations. Our results are congruent with those found in other population-based works,3 as well as a recent systematic metaanalysis,4 and a large multi-institutional work5 that was terminated early due to the interval results in favor of CEA. Despite these findings, we have tempered our observations with caution and we agree with the letter writer that the jury is still out on this “young but promising” procedure and we do not believe that it should be condemned but rather closely monitored by practitioners from diverse specialty backgrounds to ensure that its technical feasibility does not affect its indications for usage in the absence of definitive data from randomized controlled trials. Thank you again for carefully reviewing our work, on behalf of the authors. James T. McPhee, MD Mohammad H. Eslami, MD, FACS UMass Memorial Medical Center Worcester, Mass REFERENCES 1. McPhee JT, Schanzer A, Messina LM, Eslami MH. Carotid artery stenting has increased rates of postprocedure stroke, death, and resource utilization than does carotid endarterectomy in the United States, 2005. J Vasc Surg 2008;48:1442-50. 2. McPhee JT, Hill JS, Ciocca RG, Messina LM, Eslami MH. Carotid endarterectomy was performed with lower stroke and death rates than carotid artery stenting in the United States, 2003 and 2004. J Vasc Surg 2007;46:1112-8. 3. Nowygrod R, Egorova N, Giampaolo G, Anderson P, Gelijns A, Moskowitz, et al. Trends, complications, and mortality in peripheral vascular surgery. J Vasc Surg 2006;43:205–16. 4. Brahmanandam S, Ding EL, Conte MS, Belkin M, Nguyen LL. Clinical results of carotid artery stenting compared with carotid endarterectomy. J Vasc Surg 2008;47:343-9. 5. Mas JL, Chatellier G, Beyssen B, Branchereau A, Moulin T, Becquemin JP. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006;355:1660-71. doi:10.1016/j.jvs.2009.02.211