From the Southern Association for Vascular Surgery

Poststent ballooning is associated with increased periprocedural stroke and death rate in carotid artery stenting Tammam Obeid, MBBS, Dean J. Arnaoutakis, MD, Isibor Arhuidese, MBBS, MPH, Umair Qazi, MD, MPH, Christopher J. Abularrage, MD, James Black, MD, Bruce Perler, MD, MBA, and Mahmoud Malas, MD, MHS, Baltimore, Md Background: Whereas carotid endarterectomy (CEA) remains the “gold standard” treatment, given its low complication rate, carotid artery stenting (CAS) has emerged as a valid alternative in patients with prohibitive surgical risks. However, the application of CAS has been scrutinized, given its increased perioperative risk in comparison to CEA. Operators follow general guidelines in intraoperative techniques in CAS. However, few of those are evidence based. We believe that a specific outcome-driven examination of the effect of pre- and poststent deployment ballooning is warranted. The objective of this study was to analyze the effect of prestent ballooning (pre-SB) and poststent ballooning (post-SB) on hemodynamic depression (HD) and perioperative stroke or death. Methods: We performed a retrospective analysis of all patients who had CAS between 2005 and 2014 in the Vascular Quality Initiative database. Logistic regression analyses of the effect of different pre-SB and post-SB combinations on HD and the 30-day stroke and death rate were performed. We excluded patients who had no protection device, those with isolated common carotid artery lesions, and those who had no ballooning at all. The models controlled for patient age, gender, comorbidities, smoking status, symptomatic status, history of previous ipsilateral CEA, preoperative medications, and ipsilateral degree of stenosis. Results: A total of 3772 patients who underwent CAS were included for analysis. Average age of patients was 69.8 6 9.6 years, with 63% being male. The overall perioperative stroke and death rate was 3.0%. Compared with pre-SB only technique, the combined pre-SB and post-SB technique had a 2.1-fold increase in HD (odds ratio, 2.13; 95% confidence interval, 1.51-3.01; P < .001) and 2.4-fold increase in perioperative stroke and death rate (odds ratio, 2.37; 95% confidence interval, 1.01-5.62; P < .050). Conclusions: Compared with pre-SB alone, the use of post-SB increases the chances of perioperative HD and stroke and death rate in patients undergoing CAS. Post-SB should be used only in those cases with severe residual stenosis. (J Vasc Surg 2015;-:1-8.)

In the United States today, carotid endarterectomy (CEA) combined with medical management remains the “gold standard” treatment for patients with significant symptomatic and selected patients with high-grade asymptomatic carotid stenoses. Carotid artery stenting (CAS) is a valid alternative for some patients at high surgical risk. Initially, carotid stenting trials had unacceptably high complication rates of 12.1%1 and 9.9%2 for periprocedural stroke or death. Yet, with the introduction of embolic protection

From the Department of Surgery, The Johns Hopkins Medical Institutions. Author conflict of interest: none. Presented at the Plenary Session of the Thirty-ninth Annual Meeting of the Southern Association for Vascular Surgery, Scottsdale, Ariz, January 14-17, 2015. Additional material for this article may be found online at www.jvascsurg.org. Reprint requests: Mahmoud Malas, MD, MHS, FACS, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Bldg A/5, Ste 547, Baltimore, MD 21224 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2015 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvs.2015.03.069

devices (EPDs), refined techniques, better patient selection, and more experienced operators, CAS periprocedural stroke or death decreased to 4.8% in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).3 Numerous studies have elucidated parameters such as advanced age, history of coronary artery disease (CAD), symptomatic status, and hemodynamic depression (HD)4-7 as factors that worsen CAS outcomes. However, little has been published on intraoperative CAS techniques and their impact on clinical outcomes. Much variability exists today in CAS techniques, marking an area for needed improvement, particularly given the higher stroke rate in CAS compared with CEA (4.1% vs 2.3%).3 CAS is unlike other catheterization or stenting procedures during which blood flow restoration is the primary goal. Instead, the main objective during CAS should be plaque stabilization because the overwhelming majority of strokes due to carotid disease are embolic in nature.8 This unique treatment objective highlights the necessity to favor intraoperative techniques that achieve plaque stability rather than those that attempt to re-establish maximal blood flow. Consequently, substantial effort should be directed toward optimizing every step of the carotid stenting procedure for its ultimate purpose. 1

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2 Obeid et al

Angioplasty is a key procedure in CAS that carries significant embolic risk.9 It has been used to prepare a stenosed vessel for stent placement (prestent ballooning [pre-SB]) and to mitigate any residual stenosis after deployment (poststent ballooning [post-SB]). Several studies examined the effect of post-SB on hemodynamic stability and long-term in-stent restenosis.5,6,10 However, there is a lack of evidence of the optimal pre-SB and post-SB combinations and their effects on patient outcomes. In this paper, we evaluate the impact of different ballooning combinations on HD and stroke and death rates associated with CAS. METHODS We performed a retrospective analysis of all patients who underwent CAS between 2005 and 2014 documented in the Vascular Quality Initiative (VQI) database. Only de-identified information was used in this manuscript; patient data were obtained from institutes participating in VQI, which is approved by the Society for Vascular Surgery. Informed consent was waived for participating in VQI. Before analysis of the data, a quality check was performed to ensure that our patient pool was a fair representative sample of the most common CAS practices today. To achieve this goal, we included symptomatic and asymptomatic patients of any age, race, or gender who had significant stenosis in the internal carotid artery (ICA) or carotid bifurcation lesions or both. We excluded patients with isolated common carotid artery (CCA) lesions, those with no documented use of EPD, and those who did not receive any angioplasty during the CAS procedure. The patients being studied were then stratified into three groups on the basis of which ballooning they received: patients who received prestent deployment angioplasty only (pre-SB, reference group), those who received poststent deployment ballooning only (post-SB), and those who received both prestent angioplasty and poststent deployment ballooning (prepost-SB). Outcomes studied were periprocedural (same day or within 30 days of the CAS procedure) HD, stroke, and death. Stroke events included minor and major strokes, with transient ischemic attacks being excluded. HD was defined as intraoperative bradycardia requiring treatment or postoperative hypotension requiring intravenous medication. The Johns Hopkins University Institutional Review Board approved this study protocol. Statistical analysis. Multivariate logistic regression analysis was used to examine the relationship between covariates for each of the two outcomes: HD and the 30-day stroke or death rate. A total of 23 variables were included in the initial model. All appropriate theory-based continuous-categorical and categorical-categorical interaction terms were tested for, and those that were found significant are presented. For the baseline characteristics difference examination, Pearson c2 test or Fisher exact test was used for categorical variables, and the Student t-test or analysis of variance test was used for continuous variables. Stata 12.1 was used for

all calculations (StataCorp LP, College Station, Tex), and P < .05 was considered statistically significant. RESULTS A total of 5379 patients underwent CAS between 2005 and 2014. After application of our inclusion criteria, 3772 patients remained in the study population. A comparison in baseline characteristics between the different patient cohorts is presented in Table I. The age of patients ranged from 19 to 89 years (mean, 69.8 6 9.6 years), and males represented 63% of the data set. The respective median follow-up periods for the preSB, post-SB, and prepost-SB groups were 12.0, 17.2, and 17.3 months; the perioperative stroke and death rates were 2.1%, 2.4%, and 3.6%; and the long-term stroke and death rates were 7.0%, 9.8%, and 10.7%. The mean age of patients was younger between prepost-SB, post-SB, and pre-SB cohorts (70.3, 69.4, and 68.7 years, respectively; P < .0001). Statin and aspirin use was similar among the three cohorts. However, the prepost-SB group had more patients taking beta blockers and P2Y12 inhibitors compared with the post-SB and preSB groups (61% vs 58% vs 56% [P ¼ .052] and 82% vs 78% vs 81% [P ¼ .056], respectively). The prepost-SB group had significantly more patients with hypertension and CAD (91% and 40%) than the post-SB group (89% and 35%) and the pre-SB group (89% and 30%). Moreover, symptomatic status in patients was lowest in the post-SB group, followed by the prepost-SB group, and highest in the pre-SB group (33% vs 35% vs 50%, respectively; P < .0001). The degree of contralateral ICA stenosis was comparable among patients in all groups. Yet, the post-SB population had on average a higher percentage of patients with 70% to 90% ipsilateral stenosis and a lower percentage of $90% stenosis than either of the other groups. A multivariate logistic regression model was constructed to determine independent predictors of stroke and death within 30 days of carotid stenting (Table II). Advanced age was associated with 6% increase of perioperative stroke or death risk per year of age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.04-1.09; P < .0001), and symptomatic status increased the risk of stroke or death by a factor of 2.2 (OR, 2.19; 95% CI, 1.46-3.29; P < .0001). Compared with pre-SB technique, the combined prepost-SB technique was associated with a 2.4-fold increase in perioperative stroke and death rate (OR, 2.37; 95% CI, 1.01-5.62; P < .050). A second logistic regression model was constructed to determine important predictors of HD during and after CAS (Table III). Compared with the pre-SB group, the post-SB group (OR, 1.80; 95% CI, 1.26-2.57; P 500 patients, supports this theory as well. The greatest microemboli burden occurred during post-SB; furthermore, the study found that multiple microemboli during post-SB were independently associated with periprocedural cerebral deficits on multivariable regression.19 These findings support our results and show that post-SB increases embolic load during CAS and as a result the periprocedural stroke or death rate. In 2006, Gupta et al5 presented an association between HD and worse 30-day major adverse events and stroke. The authors concluded that sustained HD after CAS increased periprocedural stroke by threefold (OR, 3.05; 95% CI, 1.13-9.90; P < .03). In addition, several other studies found strong correlation between the use of postSB and HD.4,10,20,21 In our regression model, we show that prepost-SB was more than two times likely to result in HD, and post-SB alone was 1.8 times as likely to cause HD compared with pre-SB alone. This is likely the product of exaggerated and sustained pressure that the stent applies after ballooning on the carotid bulb. We believe that persistent HD can lead to increased stroke and death rate by

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means of decreased cerebral blood flow affecting watershed areas that are most vulnerable because of intracerebral arterial disease. Other patient risk factors for perioperative stroke and death that were confirmed in our study included increased age and being a male patient. Previous studies have shown that many of the risk factors for carotid stenting are similar to those for CEA. Data from the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) trial22 and the CREST trial3 demonstrated that age plays an important role in increasing perioperative complications; octogenarians have a significant increase in 30-day stroke and death rate compared with younger patients. In addition, a subanalysis of CREST23 and several other studies24,25 showed a higher risk of perioperative mortality and stroke for women compared with men. These findings are validated and quantified in our regression modeld advanced age increases the adjusted perioperative stroke and death risk by 6% per year of age, whereas male gender decreases the risk by 31%. Major limitations in our study include the exclusion of a patient subpopulation that underwent non-evidence based CAS practices. Despite similarities between the included and excluded groups in the comparison discussed earlier, other unknown factors could have resulted in selection bias. The authors plan to revisit this excluded group in the future and to conduct an in-depth examination of its characteristics and the clinical outcomes of such practices. Other limitations in this study include those that are inherent to large data sets collected by multiple individuals, such as the possibility of systematic biases, coding errors, and incomplete or missing confounding data. CONCLUSIONS Compared with pre-SB alone, the use of post-SB was associated with an increased incidence of perioperative HD and stroke or death rate in patients undergoing CAS. This finding can be explained by an increase in the pressure applied to as well as fracturing of atheromatous plaque generating distal embolization. As such, our results suggest that post-SB should be performed selectively and with caution.

AUTHOR CONTRIBUTIONS Conception and design: TO, UQ, CA, JB, BP, MM Analysis and interpretation: TO, MM Data collection: IA Writing the article: TO, DA Critical revision of the article: TO, DA, IA, UQ, CA, JB, BP, MM Final approval of the article: TO, DA, IA, UQ, CA, JB, BP, MM Statistical analysis: TO Obtained funding: Not applicable Overall responsibility: MM

REFERENCES 1. WALLSTENT (Alberts) clinical trial [Internet]. Available at: http:// www.trialresultscenter.org/study7248-WALLSTENT-(Alberts).htm http://findit.library.jhu.edu/resolve?sid¼Refworks&charset¼utf-8&__ char_set¼utf8&genre¼article&aulast¼TrialResults-center.org&atitle¼ WALLSTENT%20(Alberts)%20clinical%20trial&au¼TrialResults-center. org%20&http://findit.library.jhu.edu/images/jhu_findit.gif Find It at JH Libraries. Accessed June 25, 2013. 2. CAVATAS-CEA clinical trial [Internet]. Available at: http://www. trialresultscenter.org/study7249-CAVATAS-CEA.htmhttp://findit.lib rary.jhu.edu/resolve?sid¼Refworks&charset¼utf-8&__char_set¼utf8& genre¼article&aulast¼TrialResults-center.org&volume¼2013&issue¼ June&atitle¼CAVATAS-CEA%20clinical%20trial&au¼TrialResults-cen ter.org%20&http://findit.library.jhu.edu/images/jhu_findit.gif Find It at JH Libraries. Accessed June 25, 2013. 3. Brott TG, Hobson RW, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11-23. 4. Qazi U, Obeid TE, Enwerem N, Schneider E, White JR, Freischlag JA, et al. The effect of ballooning following carotid stent deployment on hemodynamic stability. J Vasc Surg 2014;59:756-60. 5. Gupta R, Abou-Chebl A, Bajzer CT, Schumacher HC, Yadav JS. Rate, predictors, and consequences of hemodynamic depression after carotid artery stenting. J Am Coll Cardiol 2006;47:1538-43. 6. Mlekusch W, Schillinger M, Sabeti S, Nachtmann T, Lang W, Ahmadi R, et al. Hypotension and bradycardia after elective carotid stenting: frequency and risk factors. J Endovasc Ther 2003;10:851-9; discussion: 860-1. 7. Voeks JH, Howard G, Roubin GS, Malas MB, Cohen DJ, Sternbergh WC 3rd, et al. Age and outcomes after carotid stenting and endarterectomy: the carotid revascularization endarterectomy versus stenting trial. Stroke 2011;42:3484-90. 8. Markus H. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001;124:457-67. 9. Vos JA, van den Berg JC, Ernst SM, Suttorp MJ, Overtoom TT, Mauser HW, et al. Carotid angioplasty and stent placement: comparison of transcranial Doppler US data and clinical outcome with and without filtering cerebral protection devices in 509 patients. Radiology 2005;234:493-9. 10. Bussière M, Lownie SP, Lee D, Gulka I, Leung A, Pelz DM. Hemodynamic instability during carotid artery stenting: the relative contribution of stent deployment versus balloon dilation. J Neurosurg 2009;110:905-12. 11. Bonati LH, Jongen LM, Haller S, Flach HZ, Dobson J, Nederkoorn PJ, et al. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS). Lancet Neurol 2010;9:353-62. 12. Kastrup A, Groschel K, Krapf H, Brehm BR, Dichgans J, Schulz JB. Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke 2003;34:813-9. 13. Reimers B, Schluter M, Castriota F, Tubler T, Corvaja N, Cernetti C, et al. Routine use of cerebral protection during carotid artery stenting: results of a multicenter registry of 753 patients. Am J Med 2004;116: 217-22. 14. Zahn R, Mark B, Niedermaier N, Zeymer U, Limbourg P, Ischinger T, et al. Embolic protection devices for carotid artery stenting: better results than stenting without protection? Eur Heart J 2004;25:1550-8. 15. Qureshi AI, Luft AR, Sharma M, Janardhan V, Lopes DK, Khan J, et al. Frequency and determinants of postprocedural hemodynamic instability after carotid angioplasty and stenting. Stroke 1999;30: 2086-93. 16. Gray WA, Chaturvedi S, Verta P; Investigators and the Executive Committees. Thirty-day outcomes for carotid artery stenting in 6320 patients from 2 prospective, multicenter, high-surgical-risk registries. Circ Cardiovasc Interv 2009;2:159-66.

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17. Antonius Carotid Endaterectomy, Angioplasty, and Stenting Study Group. Transcranial Doppler monitoring in angioplasty and stenting of the carotid bifurcation. J Endovasc Ther 2003;10:702-10. 18. Martin JB, Pache JC, Treggiari-Venzi M, Murphy KJ, Gailloud P, Puget E, et al. Role of the distal balloon protection technique in the prevention of cerebral embolic events during carotid stent placement. Stroke 2001;32:479-84. 19. Ackerstaff RG, Suttorp MJ, van den Berg JC, Overtoom TT, Vos JA, Bal ET, et al. Prediction of early cerebral outcome by transcranial Doppler monitoring in carotid bifurcation angioplasty and stenting. J Vasc Surg 2005;41:618-24. 20. Ullery BW, Nathan DP, Shang EK, Wang GJ, Jackson BM, Murphy EH, et al. Incidence, predictors, and outcomes of hemodynamic instability following carotid angioplasty and stenting. J Vasc Surg 2013;58:917-25. 21. Howell M, Krajcer Z, Dougherty K, Strickman N, Skolkin M, Toombs B, et al. Correlation of periprocedural systolic blood pressure changes with neurological events in high-risk carotid stent patients. J Endovasc Ther 2002;9:810-6. 22. SPACE Collaborative Group, Ringleb PA, Allenberg J, Bruckmann H, Eckstein HH, Fraedrich G, Hartmann M, et al. 30 day results from the

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SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 2006;368:1239-47. 23. Howard VJ, Lutsep HL, Mackey A, Demaerschalk BM, Sam AD 2nd, Gonzales NR, et al. Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Lancet Neurol 2011;10:530-7. 24. Rockman CB, Garg K, Jacobowitz GR, Berger JS, Mussa FF, Cayne NS, et al. Outcome of carotid artery interventions among female patients, 2004 to 2005. J Vasc Surg 2011;53:1457-64. 25. Vouyouka AG, Egorova NN, Sosunov EA, Moskowitz AJ, Gelijns A, Marin M, et al. Analysis of Florida and New York State hospital discharges suggests that carotid stenting in symptomatic women is associated with significant increase in mortality and perioperative morbidity compared with carotid endarterectomy. J Vasc Surg 2012;56:334-42. Submitted Jan 29, 2015; accepted Mar 30, 2015.

Additional material for this article may be found online at www.jvascsurg.org.

DISCUSSION Dr Matthew S. Edwards (Winston-Salem, NC). I would like to thank the Society and the program committee for the privilege of initiating the discussion of this excellent presentation by Dr Malas and colleagues from Johns Hopkins. I would like to thank the authors for providing me with a copy of the manuscript in advance of the meeting. In the presentation, the authors reported a strong association between the application of post-carotid stent angioplasty and subsequent occurrence of hemodynamic depression (HD) and stroke or death. I greatly enjoyed the presentation and the manuscript. I do, however, have several questions for the authors. 1. The reported rationale for the manuscript and presentation was to examine the impact of different ballooning combinations on HD and stroke and death rates. It would seem to me that inclusion of patients without balloon dilation during their procedure would be essential to provide a vital comparison group to support your findings, yet this group was systematically excluded from your study sample. Of the 1606 excluded records, how many were excluded due to the lack of balloon dilation as the only reason for exclusion? I believe that inclusion of these patients would greatly enhance the validity and strength of your conclusions. 2. In the manuscript, you put forth a rationale for the occurrence of adverse events, coupling the known risks of embolic-associated ischemia with the potential for exacerbation by episodes of HD. As referenced in your manuscript, a significant amount of data supports the assertion that all procedural manipulations of the plaque increase liberated debris. The rationales for preand poststent placement angioplasty differ; most view prestent angioplasty as a tool to facilitate passage of the embolic protection device or the stent. If angioplasty is needed for stent passage, the patient should (in theory) be protected from an embolic insult. Data exist within the Vascular Quality Initiative (VQI) as to why prestent angioplasty was performed (ie, for embolic protection device passage or stent passage), but it was not clear which variables were examined for inclusion in your models. Was this differentiation considered in your analysis? Also, flow reversal embolic protection has been demonstrated in a number of reports to reduce adverse event rates relative to filter or balloon occlusion techniques and offers the benefit of avoiding unprotected lesion crossing. Did you consider type of protection (broadly classified as flow reversal vs filter/occlusion) in your analysis?

3. HD is a well-known potential complicating factor of carotid stent procedures, but mixed data exist throughout the vascular surgery, neurology, and neurointerventional literature regarding the association between HD and stroke or death. Your presentation does not include the occurrence of HD as a predictor of subsequent occurrence of stroke or death. Was this analyzed, and if not, why? Given the size of your study group and the quality of the data source, demonstration of a significant association between HD and death and stroke would be an important addition to our body of knowledge regarding this problem. 4. Will your results alter your practice of uniform application of prestent angioplasty described in your prior publications on this same topic? Again, thank you for your presentation and I look forward to your answers. Dr Mahmoud Malas. Thank you, Dr Edwards, for asking these important questions. To answer the first one, out of the 1606 excluded patients, we had 336 patients with no documented ballooning at all during the procedure. We excluded this small group because it would be difficult to perform any statistically meaningful comparison to the other groups. Another reason is our a priori decision to exclude all unusual techniques in carotid artery stenting (CAS). For your second question, you ask whether we considered the reason for predilation since VQI has a variable for it. In reality, the forms used in VQI do not specifically ask the operator as to “why” predilation was performed. Instead, there is a check mark for predilation before protection device deployment and another check mark for predilation before stent deployment (after protection device deployment). While some operators perform predilation prior to protection device deployment only for severe stenosis, others do it routinely. We have no means to distinguish between these two different groups. We believe that the patients who were ballooned before any protection are at a particular disadvantage for higher risk. Thus, this group was excluded as unusual practice in CAS. As for the flow reversal, we did consider having a separate group for these patients. However, there were only 167 cases in the entire data set. Although they had a better outcome (1.8% stroke and death rate), there was a lack of power to get any statistical significance for their outcome. For your third question, HD had a complex interaction with several variables in the model despite the large sample size. Our

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decision to use HD as an outcome rather than as a predictor was simply to focus this analysis on the causal relation between timing of dilation and stroke or death. This important relation between HD and adverse outcomes of CAS is the topic of a separate research that we are conducting at the present time. Last, regarding your question about our current practice, we have changed our practice to not perform poststent ballooning a long time ago based on our personal experience. We always use protection devices (distal or reversal flow) before any manipulation

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of the lesion followed by predilation, then stenting. We accept any residual stenosis in the stent because we believe that the potential harm from dilating the stent and pushing its struts into the plaque is much higher than the potential benefit. After all, self-expanding stents continue to expand after deployment. This was the inspiration for the hypothesis behind this research. I would like to thank the Southern Association for Vascular Surgery for giving me the opportunity to present this work. I am also grateful for Dr Edwards’ excellent discussion of this paper.

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Obeid et al 8.e1

Supplementary Table (online only). Baseline characteristics comparison between included and excluded groups Variable Age, mean 6 SD Gender, male Symptomatic History of ipsilateral CEA Diabetes HTN Smoking Stroke or death

Excluded, No. (%) 1606 (30)

Included, No. (%) 3772 (70)

P value

67.7 6 11 962 (60.0) 580 (36.6) 457 (28.6) 518 (32.4) 1391 (86.9) 1215 (76.2) 74 (4.6)

69.8 6 10 2366 (62.7) 1350 (35.9) 1026 (27.2) 1389 (36.9) 3404 (90.3) 2864 (76.0) 114 (3.0)

.000 .077 .602 .279 .002 .000 .869 .003

CEA, Carotid endarterectomy; HTN, hypertension; SD, standard deviation. Bold values indicate statistical significance (P # .05).