Peter A. Schneider, MD Kaiser Hospital and Hawaii Permanente Medical Group Honolulu, Hawaii

Patient selection, techniques, & results

Transcervical carotid stenting:

DISCLOSURE Peter A. Schneider

Enter patients in studies sponsored by: Gore, Cordis, Medtronic, Silk Road, Bard, NIH, Limflow

Modest royalty: Cook

Scientific Advisory Board (non-compensated): Abbott, Medtronic, Boston Scientific, CSI

Chief Medical Officer: Intact Vascular, Cagent

National co-PI: Roadster 2, Scaffold, Confidence, In.Pact

Transfemoral CAS With Distal Filter §  Increased risk of stroke:

-  Arch manipulation causes events. -  Crossing lesion prior to filter causes events. -  Filter protection is incomplete.

§  Is there a better way? -  Avoid the arch. -  Protect before crossing. -  Protection more complete.

Device Advances and Safety How to Eliminate Microembolization

During and After Carotid Stenting

§ Cerebral Protection -  Proximal balloon occlusion -  Transcervical with reversed flow -  Combinations of protection devices

§ Stent -  Mesh coverage

§  Type of mesh §  ECA patency

Patent filed 2/17/99

Periprocedural Endpoints in CREST Twice as Many Strokes With CAS

1,081 Asymptomatic patients

CAS Events (%)

CEA Events (%)

P value

Major Stroke 3 (0.5) 2 (0.3) 0.66 Minor Stroke 12 (2.0) 6 (1.0) 0.15 Stroke and death 15 (2.5) 8 (1.4) 0.15 MI 7 (1.2) 13 (2.2) 0.76

Silver et al. Stroke 2011;42:675

1,321 Symptomatic patients

CAS Events (%)

CEA Events (%)

P value

Major Stroke 8 (1.2) 6 (0.9) 0.61 Minor Stroke 29 (4.3) 15 (2.3) 0.042 Stroke and death 40 (6.0) 21 (3.2) 0.019 MI 7 (1.0) 15 (2.3) 0.083

n engl j med 374;11 nejm.org March 17, 20161016

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

was 3.8±0.59% (1089 patients) in the stenting group and 3.4±0.98% (364 patients) in the end-arterectomy group, with a between-group differ-ence of 0.4 percentage points. The upper limit of the one-sided 95% confidence interval for the difference was 2.27 percentage points (P = 0.01 for noninferiority), which is below the prespeci-fied 3-percentage-point noninferiority margin for the primary end point, leading to the conclusion that stenting was noninferior to endarterectomy. Figure 2 shows the Kaplan–Meier analysis of freedom from death, stroke, and myocardial in-farction within 30 days and from ipsilateral stroke within 365 days in the stenting group (96.2%) and the endarterectomy group (96.6%). The periprocedural event rates through 30 days after the procedure are shown in Table 2. The 30-day rate of death or major stroke was low in both groups (0.6%). The 30-day rate of minor stroke was numerically higher in the stenting group than in the endarterectomy group (2.4% vs. 1.1%, P = 0.20), which resulted in a 30-day rate of death or any stroke of 2.9% in the stent-ing group and 1.7% in the endarterectomy group (P = 0.33).

Secondary End PointsThe analysis of the composite measure of com-plications through 30 days after the procedure is shown in Table 2. The overall event rate for this

composite measure was 2.8% in the stenting group and 4.7% in the endarterectomy group (P = 0.13); the rate of cranial-nerve injury was 0.1% in the stenting group and 1.1% in the end-arterectomy group (P = 0.02). The rates of acute device success and procedural success in the stenting group were 98.4% and 95.6%, respective-ly. The rate of freedom from clinically driven target-lesion revascularization at 6 months was 99.8% in the stenting group and 99.7% in the endarterectomy group (P = 0.72); at 1 year, the rates were 99.4% and 97.4%, respectively (P = 0.005).

The estimated survival rate at 5 years was 87.1% in the stenting group and 89.4% in the endarterectomy group (P = 0.21) (Fig. 3B). The rate of freedom from non–procedure-related ipsi-lateral stroke through 5 years was 97.8% in the stenting group and 97.3% in the endarterectomy group (P = 0.51) (Fig. 3A). The rate of freedom from any stroke (ipsilateral or contralateral) through 5 years was 93.1% in the stenting group and 94.7% in the endarterectomy group (P = 0.44) (Fig. 3C).

Discussion

Several multicenter, randomized clinical trials of carotid endarterectomy have provided data show-ing the usefulness of surgical revascularization for the treatment of patients with asymptomatic

Figure 2. Kaplan–Meier Analysis of Freedom from the Primary Composite End Point.

Shown is the Kaplan–Meier survival curve for freedom from death, stroke, and myocardial infarction within 30 days and from ipsilateral stroke within 365 days after the procedure in the intention-to-treat population.

Even

t-fre

e Su

rviv

al (%

)100

80

90

70

60

50

00 50 7525 100 125 150 200 225 250 275175 300 325 350 375

Day

0 CensoredP=0.69 (by Wilcoxon rank-sum test)

DaysStenting (no. at risk)Endarterectomy (no. at risk)

1089364

1067354

1016325

956309

1–300 31–180 181–365

StentingEndarterectomy

The New England Journal of Medicine Downloaded from nejm.org at KAISER PERMANENTE on May 2, 2016. For personal use only. No other uses without permission.

Copyright © 2016 Massachusetts Medical Society. All rights reserved.

Freedom from Primary Composite Endpoint: Stroke, Death, MI

ACT I: Asymptomatic Carotid Stenosis Prospective Randomized Controlled Trial of 1,453 patients

Rosenfield et al. N Engl J Med 2016;374:1011

Stroke/Death at 30 days CAS 2.9%, CEA 1.7%

Too Many DW-MRI Hits

thereby avoiding the arch manipulation risk, and eliminatesinstrumentation for external carotid artery occlusion.Additionally, it also reduces the risk of complicationsassociated with CEA.

The clinical significance of the appearance of post-procedural silent ischaemic cerebral lesions is unknown.

Very few studies have described the long-term fate of post-operative DWI-detected ischaemic lesions. Whether thesesilent ischaemic lesions cause permanent brain damagewith cognitive impairment or merely transient sequelaeremains unclear. Indeed, some of these lesions may resolvewithin months, as reported in other series.47 However,

Table 3 Incidence of Ischemic Infarction with Carotid Artery Stenting.

Author Year Procedures (N) Strokes (N) New Ischemic lesions on DW-MRI

Ipsilateral Contralateral Any

Lovblad8 2000 19 2 4 (21,05%)Jaeger9 2001 20 0 3 2 5(25 %)Jaeger10 2002 70 1 20 6 26 (37,14%)Schluter11 2003 44 1 8 2 10 (22,72%)Gauvrit12 2004 22 1 2 0 2 (9,09%)Poppert13 2004 41 1 22 4 22 (53,65%)Flach14 2005 21 1 9 2 9 (42,85%)Roh15 2005 18 2 8 (44,44%)Cossottini16 2005 52 1 16 (30,76%)Hammer17 2005 53 2 14 13 21 (39,62%)Hauth18 2005 105 0 22 (20,95%)Rosenkranz19 2006 27 0 6 2 8 (29,62%)Du Mesnil20 2006 50 1 14 7 19 (38%)Maleux21 2006 53 0 17 10 22 (41,50%)McDonell22 2006 107 8 23 (21,49%)Pinero23 2006 162 1 22 9 28 (17,28%)Kastrup24 2006 206 11 113 38 126 (61,16%)Asakura25 2006 45 1 14 13 20 (44,44%)Iihara26 2006 92 7 32 (34,78%)Grunwald27 2006 10 0 3 1 4 (40%)Rapp28 2007 54 2 35 11 36 (59,01%)Lacroix29 2007 61 2 20 10 26 (42,62%)Tedesco30 2007 27 2 16 10 19 (70,37%)Skelland31 2009 30 2 6 0 6 (20%)Taha32 2009 98 3 35 20 42 (42,85%)

Table 4 Incidence of Ischemic Infarction with Carotid Endarterectomy.

Author Year Procedures (N) Strokes (N) New Ischemic lesions on DWI

Ipsilateral Contralateral Any

Jansen33 1994 40 1 4 0 4 (10%)Cantelmo34 1998 78 1 7 0 7 (8,97%)Barth35 2000 48 0 2 0 2 (4,17%)Feiwell36 2001 25 0 1 0 1 (4%)Forbes37 2001 18 1 0 0 0 (0 %)Tomczak38 2001 51 0 6 0 6 (11,76%)Muller39 2003 33 1 9 (27,28%)Wolf40 2004 33 1 8 0 8 (24,25%)Poppert13 2004 88 2 15 0 15 (17,04%)Flach14 2004 23 2 2 0 2 (8,69%)Roh15 2005 26 1 1 0 1 (3,85%)Iihara25 2006 139 3 13 (9,36%)Inoue41 2006 72 1 3 (4,17%)Lacroix28 2007 60 2 7 1 7 (11,67%)Tedesco29 2007 20 0 0 0 0 (0%)Skejelland30 2009 61 0 2 0 2 (3,28%)

664 J.I. Leal et al.

thereby avoiding the arch manipulation risk, and eliminatesinstrumentation for external carotid artery occlusion.Additionally, it also reduces the risk of complicationsassociated with CEA.

The clinical significance of the appearance of post-procedural silent ischaemic cerebral lesions is unknown.

Very few studies have described the long-term fate of post-operative DWI-detected ischaemic lesions. Whether thesesilent ischaemic lesions cause permanent brain damagewith cognitive impairment or merely transient sequelaeremains unclear. Indeed, some of these lesions may resolvewithin months, as reported in other series.47 However,

Table 3 Incidence of Ischemic Infarction with Carotid Artery Stenting.

Author Year Procedures (N) Strokes (N) New Ischemic lesions on DW-MRI

Ipsilateral Contralateral Any

Lovblad8 2000 19 2 4 (21,05%)Jaeger9 2001 20 0 3 2 5(25 %)Jaeger10 2002 70 1 20 6 26 (37,14%)Schluter11 2003 44 1 8 2 10 (22,72%)Gauvrit12 2004 22 1 2 0 2 (9,09%)Poppert13 2004 41 1 22 4 22 (53,65%)Flach14 2005 21 1 9 2 9 (42,85%)Roh15 2005 18 2 8 (44,44%)Cossottini16 2005 52 1 16 (30,76%)Hammer17 2005 53 2 14 13 21 (39,62%)Hauth18 2005 105 0 22 (20,95%)Rosenkranz19 2006 27 0 6 2 8 (29,62%)Du Mesnil20 2006 50 1 14 7 19 (38%)Maleux21 2006 53 0 17 10 22 (41,50%)McDonell22 2006 107 8 23 (21,49%)Pinero23 2006 162 1 22 9 28 (17,28%)Kastrup24 2006 206 11 113 38 126 (61,16%)Asakura25 2006 45 1 14 13 20 (44,44%)Iihara26 2006 92 7 32 (34,78%)Grunwald27 2006 10 0 3 1 4 (40%)Rapp28 2007 54 2 35 11 36 (59,01%)Lacroix29 2007 61 2 20 10 26 (42,62%)Tedesco30 2007 27 2 16 10 19 (70,37%)Skelland31 2009 30 2 6 0 6 (20%)Taha32 2009 98 3 35 20 42 (42,85%)

Table 4 Incidence of Ischemic Infarction with Carotid Endarterectomy.

Author Year Procedures (N) Strokes (N) New Ischemic lesions on DWI

Ipsilateral Contralateral Any

Jansen33 1994 40 1 4 0 4 (10%)Cantelmo34 1998 78 1 7 0 7 (8,97%)Barth35 2000 48 0 2 0 2 (4,17%)Feiwell36 2001 25 0 1 0 1 (4%)Forbes37 2001 18 1 0 0 0 (0 %)Tomczak38 2001 51 0 6 0 6 (11,76%)Muller39 2003 33 1 9 (27,28%)Wolf40 2004 33 1 8 0 8 (24,25%)Poppert13 2004 88 2 15 0 15 (17,04%)Flach14 2004 23 2 2 0 2 (8,69%)Roh15 2005 26 1 1 0 1 (3,85%)Iihara25 2006 139 3 13 (9,36%)Inoue41 2006 72 1 3 (4,17%)Lacroix28 2007 60 2 7 1 7 (11,67%)Tedesco29 2007 20 0 0 0 0 (0%)Skejelland30 2009 61 0 2 0 2 (3,28%)

664 J.I. Leal et al.

CAS: up to 70%

CEA: up to 27%

Leal et al. Eur J Vasc Endovasc Surg 2010;39:661

2-3 times as many DW-MRI hits for CAS than for CEA. Most are temporary, not associated with neurologic deficits. Use as a surrogate end point for neurological risk

ProximalBalloonOcclusion

MAE Total 2.7% Major Stroke 0.9% Minor Stroke 1.4% Death 0.9% MI 0 TIA 0.9% Ansel et al. Catheter Cardiovasc Interv 2010;76:1

ArmourTrial(n=220)

Proximal Protection Mo-Ma Balloon Occlusion vs Filter

A recent comparative trial between a filter device(Angioguard, Cordis, East Bridgewater, New Jersey)and the Mo.Ma system showed a lack of a significantdifference in the proportion of patients with newischemic lesions (63.3% vs. 66.7%; p ¼ NS). Despitethis, the number of ischemic cerebral lesions per pa-tient was significantly lower in the Mo.Ma group(a median of 6 lesions per patient vs. a median of 10in the Angioguard group, p < 0.001). One patient hada minor stroke during CAS (1.66%) in the Angioguardgroup (14).

Opposite results were recently observed in asimilar single-center trial comparing flow-reversalEPD (n ¼ 21) to filter EPD (n ¼ 19); a significantreduction in the incidence (15.8% vs. 47.6%,p ¼ 0.03), number (0.73 vs. 2.6, p ¼ 0.05), and size(0.81 vs. 2.23 mm, p ¼ 0.05) of new ischemic lesionswere observed when filter EPDs were used (15).

This meta-analysis pooled all the available dataand analyzed the incidence of new ischemic lesionsdetected at DW-MRI following CAS. We found that thenumber of lesions per patient who underwentproximal-protected CAS is lower when compared withdistal-protected CAS. The association of proximalprotection with a reduced distal embolization isconsistent at the contralateral site.

STUDY LIMITATIONS. One of the most impor-tant pitfalls of the primary studies included in thismeta-analysis is represented by the lack of informa-tion about the experience of physicians performingCAS procedures. It has now been clearly demon-strated that the number of procedures performed incatheterization laboratories influences the outcomeof CAS procedures (23,24). A different level of expe-rience on the use of specific EPDs might contribute to

FIGURE 2 Incidence of New Ischemic Lesions/Patient at DW-MRI

Forrest plot representing the pooled estimate analysis for overall incidence of new ischemic lesions/patient detected at diffusion-weightedmagnetic resonance imaging (DW-MRI). CI ¼ confidence interval; ES ¼ effect size.

FIGURE 3 Incidence of New Ischemic Lesions at the Contralateral Site at DW-MRI

Forrest plot representing the pooled estimate analysis for overall incidence of new ischemic lesions at the contralateral site at DW-MRI.Abbreviations as in Figure 2.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 7 , N O . 1 0 , 2 0 1 4 Stabile et al.O C T O B E R 2 0 1 4 : 1 1 7 7 – 8 3 Embolic Protection During Carotid Artery Stenting

1181

Incidence of new ischemic lesions by DW-MRI

Stabile et al. JACC Cardiovasc Interv 2014;7:1177

Fewer MRI Hits with Proximal Protection Using MoMa

).N<O/.,%P%32%+/E%B*373823>%+2%Q$Q%&'((%

Z)[)\L)

PROFI: Prospective Randomized Trial of Proximal Balloon Occlusion vs Filter

Bijuklic K et al. J Am Coll Cardiol 2012;59:1383

DW-MRI Lesions N=62

Proximal Protection (MoMa) versus Distal Filter Stroke Event and Location

Giri et al. JACC Cardiovasc Interv 2015;8:609 whereas 1 trial noted more dwMRI lesions with P-EPDs. Each trial studied only 40 to 62 patients, soconclusions about stroke rates could not be made.Our results suggest that if P-EPDs do indeed decreasecerebral microemboli during CAS, this does notnecessarily translate into robust differences in clin-ical outcomes.

A recently published meta-analysis reported30-day clinical outcomes of nearly all the reportedpatients to date in clinical protocols who received aP-EPD during CAS (12). The authors reported a 30-daystroke/death rate of 2.1%. Importantly, these resultsmay not be generalizable because all patients weretreated at a limited number of experienced centers,most within the context of industry-sponsored clin-ical trials. Additionally, there were no control groupsin the analyzed studies, making it impossible to drawconclusions about relative therapy effectiveness.Nevertheless, it is interesting that our observed30-day stroke/death rate of 2.5% is fairly consistentwith these results.

Certain characteristics, such as symptomatic lesionstatus, have been advocated by expert operators asreasons to choose a P-EPD over an F-EPD. The symp-tomatic subgroup did not show particular benefit of P-EPD use over F-EPD use in the current analysis.Additionally, we did not observe reduced rates ofipsilateral stroke with P-EPDs, the major presumedbenefit of P-EPD use. It should be noted, however, thatno signal of harm was noted with the use of P-EPDs,and there were trends toward improved outcomes at30 days that did not meet statistical significance. Assuch, it is reasonable to defer to operator preference,experience, and judgment in specific clinical scenarioswhen choosing the type of embolic protection for anindividual CAS procedure.

Because of the slow adoption of P-EPDs in theUnited States, the proximal protection group in thisstudy was much smaller than the F-EPD group. Weattempted to account for any selection bias with ourpropensity-matched analysis. Still, we cannot ruleout the influence of unmeasured confounders in this

analysis. These include operator experience, operatorspecialty, and anatomic characteristics (e.g., externalcarotid artery stenosis precluding effective proximalprotection device placement) that may have biasedthe choice of protection device. Next, it is possiblethat operators were less familiar with P-EPD,implying that the currently observed stroke rates inP-EPD–treated patients may decrease over time.However, in an analysis of the first 295 proceduresperformed with P-EPDs versus the second 295 pro-cedures performed, there were no significant differ-ences in stroke rates (data not shown). Finally,despite being the largest national registry of CAS, thenumber of P-EPD devices used in the registry wasmodest, and the study may be underpowered todetect potentially meaningful differences in out-comes between the devices. However, given the ratesof the primary endpoint observed in our cohort, arandomized trial of >34,000 subjects would berequired to detect a significant difference between P-EPDs and F-EPDs with 80% power (a trial with adesign on the basis of our observed 30-day eventrates would require >6,000 patients). There are noknown plans to organize such an effort, so it is likelythat the current data will remain the best availableevidence on this issue for the foreseeable future.

CONCLUSIONS

Use of a P-EPD during CAS was associated with simi-larly low rates of in-hospital stroke/death comparedwith F-EPD use in the first comparative analysis per-formed of this issue. An adequately powered ran-domized trial comparing clinical outcomes betweenthese devices is unlikely to be feasible.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Jay Giri, Hospital of the University of PennsylvaniaCardiovascular Medicine Division, Gates Pavilion, 9thFloor, 3400 Spruce Street, Philadelphia, Pennsylva-nia 19104. E-mail: Giri.jay@gmail.com.

TABLE 3 In-Hospital Strokes Grouped by Involved Territory

Before Propensity Matching After Propensity Matching

F-EPD(n ¼ 9,656)

P-EPD(n ¼ 590) p Value

F-EPD(n ¼ 2,032)

P-EPD(n ¼ 508) p Value

All strokes 209 (2.2) 9 (1.5) 0.296 33 (1.6) 8 (1.6) 0.937

Ipsilateral strokes 139 (1.4) 4 (0.7) 0.126 21 (1.0) 4 (0.8) 0.615

Contralateral strokes 26 (0.3) 2 (0.3) 0.675 5 (0.2) 2 (0.4) 0.633

Vertebral/unknown strokes 44 (0.5) 3 (0.5) 0.751 7 (0.3) 2 (0.4) 0.99

Values are n (%).

Abbreviations as in Table 1.

PERSPECTIVES

P-EPDs have theoretical advantages that may make

them superior to distal F-EPDs for stroke prevention

during CAS. In more than 10,000 patients treated

with embolic protection for CAS, the use of P-EPDs

was associated with low rates of in-hospital stroke/death similar to those with F-EPDs. Given the

observed low event rates in the current analysis, an

adequately powered randomized trial examining this

issue is unlikely to be feasible.

Giri et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 4 , 2 0 1 5

Proximal Versus Distal EPD for CAS A P R I L 2 0 , 2 0 1 5 : 6 0 9 – 1 5

614

Stroke Location

10,200 patients in the NCDR CARE Registry

Filter Proximal Balloon

53% of strokes in filter cases and 37% of strokes in proximal balloon cases were non-ipsilateral

Articles

www.thelancet.com/neurology Published online February 26, 2010 DOI:10.1016/S1474-4422(10)70057-0 5

62 (50%) of 124 patients in the stenting group had new DWI lesions on post-treatment scans compared with 18 (17%) of 107 patients in the endarterectomy group (OR 5·21, 95% CI 2·78–9·79; p<0·0001, adjusted for interval between treatment and post-treatment scan; table 4). There were non-signifi cant imbalances between treatment groups in the proportion of patients with hemispheric ischaemic stroke as qualifying event (55 [44%] of 124 in the stenting group and 39 [36%] of 107 in the endarterectomy group, p=0·223) and interval between most recent ipsilateral event and treatment (median 37 days [IQR 14–82] in the stenting group and 45 [23–85] in the endarterectomy group, p=0·123; table 2). In a post-hoc comparison adjusted for these variables in addition to interval between treatment and post-treatment scan, the OR for new DWI lesions was 5·30 (95% CI 2·80–10·05, p<0·0001). In patients who had pretreatment and post-treatment scans within the prespecifi ed time limits, 58 (49%) of 118 patients in the stenting group and 15 (18%) of 85 patients in the endarterectomy group had new DWI lesions after treatment (adjusted OR 4·84, 95% CI 2·45–9·55; p<0·0001).

66 patients were studied in 3 Tesla scanners (37 in the stenting group and 29 in the endarterectomy group) and 165 in 1·5 Tesla scanners. Lesions were detected in 29 (44%) of 66 patients scanned with 3 Tesla compared with 51 (31%) of 165 patients scanned with 1·5 Tesla (p=0·06).

In eight of 62 patients with positive DWI after stenting, lesions were associated with symptoms of an ischaemic hemispheric stroke between initiation of treatment and the post-treatment scan, and one patient had an ipsilateral retinal stroke before the scan (table 4). In the other 53 patients with stents and new DWI lesions, no ischaemic events happened up to the time of the scan; however, one patient had an ischaemic stroke 4 days after the scan, and two had transient ischaemic attacks (26 and 28 days after the scan). In addition, one patient without new DWI lesions on the post-treatment scan had a transient ischaemic attack 19 days after the scan. In the endarterectomy group, three of 18 patients with new DWI lesions had ischaemic hemispheric strokes, whereas 15 did not have any ischaemic events up to the time of the scan; however, two patients who did not have any new lesions on post-treatment DWI had haemorrhagic strokes 1 and 3 days after the scan. No hemispheric ischaemic event occurred between treatment and the post-treatment scan without a corresponding lesion on DWI in any of the 231 patients included in the primary analysis.

In patients with hemispheric stroke as the qualifying event, 33 (60%) of 55 in the stenting group and four (10%) of 39 in the endarterectomy group had new DWI lesions on post-treatment scans (adjusted OR 15·04, 95% CI 4·38–51·67), whereas in those with a retinal ischaemic event or transient ischaemic attack as the qualifying event, 29 (42%) of 69 in the stenting group and 14 (21%) of 68 in the endarterectomy group had new DWI lesions (adjusted OR 2·89, 1·34–6·22; interaction p=0·025;

fi gure 2). In patients treated at a centre with a policy of using cerebral protection devices, 37 (73%) of 51 in the stenting group and eight (17%) of 46 in the endarterectomy group had new DWI lesions on post-treatment scans (adjusted OR 12·20, 95% CI 4·53–32·84), whereas in those treated at a centre with a policy of unprotected stenting 25 (34%) of 73 patients in the stenting group and ten (16%) of 61 in the endarterectomy group had new lesions on DWI (adjusted OR 2·70, 1·16–6·24; interaction p=0·019). Both interactions remained signifi cant after adjustment for each other (p=0·040 and p=0·038, respectively). In the stenting group, cerebral protection

Carotid stenting (n=124)

Carotid endarterectomy (n=107)

OR (95% CI) p*

Any stroke or death 11 (9%) 5 (5%) 1·99 (0·70–5·66) 0·300

All cause death 1 (1%) 0 ·· ··

Any stroke 10 (8%) 5 (5%) 1·79 (0·62–5·17) 0·423

Stroke pathology

Ischaemic 10 (8%) 3 (3%) ·· ··

Haemorrhagic 0 2 (2%) ·· ··

Stroke severity

Non-disabling 7 (6%) 2 (2%) ·· ··

Disabling 3 (2%) 3 (3%) ·· ··

Fatal 0 0 ·· ··

TIA 3 (2%) 0 ·· ··

Ischaemic stroke or TIA 13 (10%) 3 (3%) 4·06 (1·20–13·63) 0·035

Data are number (%). TIA=transient ischaemic attack. *Fisher’s exact test.

Table 3: Clinical outcome within 30 days of treatment

Carotid stenting (n=124)

Carotid endarterectomy (n=107)

OR (95% CI) p*

At least one new lesion 62 (50%) 18 (17%) 4·94 (2·67–9·16)†5·21 (2·78–9·79)‡

<0·0001<0·0001

Single lesion 18 (15%) 9 (8%) ·· ··

Multiple lesions 44 (35%) 9 (8%) ·· ··

Location of lesions

Ipsilateral carotid circulation only 34 (27%) 14 (13%) ·· ··

Ipsilateral carotid and non-ipsilateral (contralateral carotid or vertebrobasilar) circulations

22 (18%) 3 (3%) ·· ··

Non-ipsilateral (contralateral carotid or vertebrobasilar) circulations only

6 (5%) 1 (1%) ·· ··

Ischaemic events in patients with new DWI lesions§

9 (7%) 3 (3%) ·· ··

Hemispheric stroke 8 (6%) 3 (3%) ·· ··

Retinal infarct 1 (1%) 0 ·· ··

TIA 0 0 ·· ··

None 53 (43%) 15 (14%) ·· ··

Data are number (%). DWI=diff usion-weighted imaging. TIA=transient ischaemic attack. *Logistic regression. †Unadjusted. ‡Adjusted for interval between treatment and post-treatment scan. §Events occurring between start of treatment and post-treatment scans only. No ischaemic event occurred between the start of treatment and the post-treatment scan in patients without new DWI lesions.

Table 4: New DWI lesions on post-treatment scans

Bonati et al. Lancet Neurology 2010;1016:1474

ICSS MRI Subset

Articles

www.thelancet.com/neurology Published online February 26, 2010 DOI:10.1016/S1474-4422(10)70057-0 7

patients (8%) in the endarterectomy group (adjusted OR 5·93 [95% CI 2·25–15·62]; p=0·0003; table 5). Six patients in the stenting group and one in the endarterectomy group had new hyperintense DWI lesions on the 1-month follow-up scan.

The two reviewers initially disagreed and reached consensus on the presence or absence of hyperintense DWI lesions in two of 231 pretreatment scans that were included in the primary analysis, eight of 231 post-treatment scans, and one of 161 scans at 1-month follow-up. In addition, there was initial disagreement on the number of lesions in 25 of the 80 patients who had new DWI lesions on post-treatment scans.

DiscussionIn this MRI substudy of ICSS, about three times more patients had new ischaemic lesions on DWI after stenting than after endarterectomy, and the risk of cerebral ischaemia was higher among patients undergoing stenting with cerebral protection devices than without.

Non-randomised studies have suggested a higher rate of postprocedural ischaemic lesions on DWI after

stenting compared with endarterectomy:8–16 in a meta-analysis of these studies the aggregate OR of new ischaemic lesions after treatment was 6·71 (95% CI 4·57–9·87) favouring endarterectomy (fi gure 4). However, whether this was because more patients who had high cardiovascular risk profi les were assigned to stenting is unclear. The OR for DWI lesions in our randomised study was very similar, arguing against such a bias.

At most centres in ICSS, patients were sent to neurological wards after stenting, whereas patients who had endarterectomy were transferred to high-dependency units or were sent to surgical wards for care after treatment. Thus, non-disabling strokes might have been detected more readily among patients who had stenting than among those who had endarterectomy. However, the results of the ICSS-MRI study confi rm an increased risk of cerebral ischaemia associated with stenting in comparison with endarterectomy by using a separate, blinded assessment of MRI; thus it is unlikely that ascertainment bias caused the diff erence in non-disabling strokes between the two groups.

Among the 62 patients in the stenting group who had new DWI lesions after treatment, 44 (71%) had more than one lesion, and 28 (45%) had lesions in the contralateral carotid or vertebrobasilar circulation (mostly in addition to lesions in the ipsilateral carotid circulation). These results support the notion of an embolic pathogenesis of cerebral ischaemia.17 Embolism might have happened at any stage of the stent procedure, including angiography before stenting.18 Thrombotic material or atherosclerotic debris dislodged during the stenting procedure seems to result in single or multiple small emboli, which might manifest as stroke if a large enough volume of eloquent brain tissue is aff ected.

The diff erential risk of cerebral ischaemia was modifi ed by the type of the most recent ipsilateral event before randomisation: the proportion with DWI lesions associated with stenting was smaller for patients enrolled after a transient ischaemic attack or a retinal ischaemic event than for patients who were enrolled after a hemispheric stroke. This pattern might have developed because patients with strokes have less stable plaques compared with those presenting with other ischaemic symptoms, a hypothesis that is supported by a histological study of symptomatic carotid plaques.19 Thus, increased

Figure 3: Distribution of DWI lesion volumes on post-treatment scans according to whether or not focal neurological defi cits occurredDWI=diff usion-weighted imaging.

<0·10 0·10–0·25

Num

ber o

f pat

ient

s

0·25–0·500

5

10

15

20

25

30

35

40

0·50–1·00

Total volume of DWI lesions on post-treatment scan (mL)

1–5 >5

Hemispheric ischaemic strokeNo focal neurological deficit

Carotid stenting (n=86)

Carotid endarterectomy (n=75)

OR (95% CI) p*

At least one new ischaemic lesion on post-treatment DWI 44 (51%) 10 (13%) ·· ··

New hyperintensity on FLAIR at 1-month follow-up at site of at least one post-treatment DWI lesion

28 (33%) 6 (8%) 5·55 (2·15–14·33) 5.93 (2·25–15·62)

0·0004†0·0003‡

New ischaemic lesion on DWI at 1-month follow-up not seen on post-treatment scan

6 (7%) 1 (1%) 5·55 (0·65–47·19) 0·117†

Data are number (%) or OR (95% CI). Patients with completed pretreatment, post-treatment and 1-month follow-up MRI scans are included. DWI=diff usion-weighted imaging. FLAIR=fl uid-attenuated inversion recovery imaging. *Logistic regression. †Unadjusted. ‡Adjusted for interval between treatment and post-treatment scan.

Table 5: MRI fi ndings at 1-month follow-up

Microembolization with Endovascular Therapy DW-MRI Hits

Larger DW-MRI volume=stroke CAS: About 3X as many hits as CEA. 46% of patients with hits had non-ipsilateral hits.

sphere supplied by the study carotid artery were classified asipsilateral.

As the North American Symptomatic Carotid Endar-terectomy Trial (NASCET) study evaluated symptomaticnonoctogenarians, in comparing the outcomes in CAPTUREto those from NASCET only data from symptomatic patientsunder 80-year-old cohort was used. It should be recognizedthat only patients of normal surgical risk were enrolled in theNASCET CEA trial, whereas CAPTURE was aimed at pa-tients of high surgical risk; this limits a direct comparison ofthe data.

RESULTS

Enrollment and Patient CharacteristicsBetween October 2004 and March 2006, 3500 high

surgical risk patients were enrolled by 353 interventionalistsat 144 sites distributed throughout the United States. Includedin this analysis are patients in whom CAS with embolicprotection was attempted, whether or not it was successfullyplaced. All consecutive patients were included in this analysisif they had 30-day follow-up or had an endpoint event before30 days.

The baseline demographics of patients in CAPTUREare shown in Table 1. The mean age of the patients was 73years, and approximately 24% of the total cohort was !80years. Recent neurologic symptoms such as transient isch-emic attack, amaurosis fugax or stroke were present in 14%of the patients treated. In addition the mean target lesionstenosis was 85%, and severe (!80%) stenosis was present in92% of asymptomatic patients and 76% of symptomaticpatients. Demographics were similar for symptomatic andasymptomatic patients. One hundred sixty-eight (168) pa-tients experienced 170 strokes. Two patients each experi-enced more than one stroke. Approximately 36% (60 of 168)of all strokes were noted in patients !80 years of age, and26% (43 of 168) were noted in symptomatic patients. Bothage and symptomatic status has previously been reported tobe significant predictors of outcome by logistic regression.22

Demographics were also similar for patients experiencingipsilateral and nonipsilateral strokes.

Thirty-Day Primary End PointFor the purposes of endpoint analysis, patients having 2

procedures within 30 days are considered as 1 patient. There-fore, 45 patients are counted only once in the denominator,for a total of 3500 intent-to-treat internal and common carotidartery stenting patients. The 30-day primary combined end-point rate of death, all stroke or myocardial infarction amongall patients enrolled in CAPTURE is 6.3% (Table 2), withdeath and all stroke 5.7%, and death and major stroke 2.9%.

Stroke AnalysisOne hundred sixty-eight patients experienced 170

strokes in this cohort of 3500 patients. Two patients each had2 strokes. The overall stroke rate was 4.8%. The majority ofthe strokes were minor (2.9% out of 3500 patients; Fig. 1).Eighty-eight percent (88%; 150 of 170) of the strokes wereischemic, the remainder hemorrhagic. The stroke incidencewas higher in symptomatic patients and in octogenarians. Insymptomatic patients (n ! 482) the stroke rate was 8.9%,whereas in asymptomatic patients (n ! 3018) the stroke ratewas 4.1%. Seven percent (7%) of the octogenarians (n ! 829)experienced a stroke, whereas 4% of nonoctogenarians (n !2671) experienced a stroke.

Strokes affecting the cerebral hemisphere supplied bythe study carotid artery were classified as ipsilateral (Fig. 1).Strokes affecting the contralateral side or the posterior circu-lation were classified as nonipsilateral. Eighty-two percent ofthe strokes were ipsilateral (139 of 170) and 18% were

TABLE 2. 30-Day Outcomes

EventCAPTURE(N ! 3500)

Death, stroke, and MI* 6.3%All stroke and death* 5.7%Major stroke and death* 2.9%Death 1.8%All stroke 4.8%Major stroke 2.0%Minor stroke 2.9%MI 0.9%

*Hierarchical: includes only the most serious event for each patient and includesonly each patient’s first occurrence of each event.

FIGURE 1. Stroke cohort flowchart.

TABLE 1. Patient Demographics

CharacteristicCAPTURE(N ! 3500)

All Strokes(N ! 168)

Non Stroke(N ! 3332)

Mean Age (Yr) 72.7 75.8 72.6Age "80 23.7% 35.7% 23.1%% Symptomatic (n ! 482) 13.8% 25.6% 13.2%% Male 61.1% 54.2% 61.4%Diabetes mellitus 34.7% 33.5% 34.7%Hypertension 88.3% 92.2% 88.2%Hypercholesterolemia 77.8% 80.4% 77.6%CHF 16.5% 19.0% 16.4%Anatomic 10.7% 9.5% 10.7%Current smoker 20.9% 15.2% 21.2%PVD 35.6% 33.9% 35.7%

Fairman et al Annals of Surgery • Volume 246, Number 4, October 2007

© 2007 Lippincott Williams & Wilkins210Capture Registry. Fairman et al. Ann Surg 2007;246:208

CAS with Distal Filter Capture Registry: 18% of stroke non-ipsilateral

SAPPHIRE RCT and CASES Post-market Up to 33% of stroke non-ipsilateral

The arch is a problem

Kassavin et al. Eur J Vasc Surg 2017;65:271

Stenting Study (ICSS), patients undergoing CAS withEPDs had a 73% incidence of new lesions on diffusion-weighted magnetic resonance imaging compared with17% in the CEA group.17 In a study validating the use oftranscranial Doppler ultrasound for intraproceduralmonitoring of embolic events during CAS, there was anincrease in embolic signals during lesion crossing, beforedilation, in stent placement, and after dilation in the CAS

group using EPDs. Compared with the EPD group, thesignal count was higher in the FRD group only duringdevice removal.18

Transcervical access may reduce the incidence of cere-bral embolization by avoiding a tortuous and atheroscle-rotic thoracic aortic arch. Up to 8% of strokes occur onthe contralateral side of intervention,3 suggesting thatembolization occurs during manipulation of wires andcatheters within this area. It is thought that the greatertortuosity and atherosclerotic burden in the aortic arch

Fig 1. The 30-day stroke rate in a sample of carotid artery stenting (CAS) registries, cohort studies, and ran-domized controlled trials. The gray markers indicate studies performed predominantly with embolic protectiondevices (EPDs). The blue markers indicate studies performed with proximal occlusion devices (PODs), with andwithout flow reversal, through femoral or carotid access.

Fig 2. Medtronic Mo.Ma device: 1, Exit port of workingchannel; 2, distal, external carotid artery balloon; 3, prox-imal, common carotid artery balloon; 4, port for injection,pressure monitoring, and aspiration; 5, entry port of theworking channel; 6, inflation port for distal balloon; 7,inflation port for proximal balloon.

Fig 3. Silk Road Enroute Transcarotid NeuroprotectionSystem. Top, Angled tip transcarotid arterial sheath anddilator. Middle, Venous return sheath and dilator. Bottom,Flow controller with integrated filter.

272 Kassavin and Clair Journal of Vascular SurgeryJanuary 2017

Downloaded for Anonymous User (n/a) at Kaiser Permanente from ClinicalKey.com by Elsevier on March 16, 2018.For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

Proximal Protection MoMa Balloon Occlusion or TCAR (transcervical approach)

ProximalProtec6onwithReversedFlowTCAR-Transcaro6dApproach

First commercial case in US

More invasive than transfemoral Less invasive than endarterectomy Avoid the arch Protection prior to crossing More efficient particle capture

Blood flow is temporarily

reversed in the carotid arteries

Dynamic Flow Controller &

Integrated 200µ Filter

High / Low / Stop

Blood flow is returned

to femoral veinWorking channel for interventional

devices ENROUTE® Transcarotid Stent

System (57cm)

Transfemoral CAS vs CEA vs TCAR

252 Journal of Endovascular Therapy 23(2)

CASfr and CEA already show less embolization in the pre-protection phase before the embolic protection device (EPD), shunt, or flow reversal are in place. This can be explained by the fact that CEA and CASfr with a direct cer-vical approach are able to treat the lesion site directly, while in CASdp, manipulation in the aortic arch and the origin of the CCA may dislodge emboli that migrate to the brain. This is in line with other studies suggesting that these con-tralateral DW-MRI lesions after CASdp3,7,20 are most likely caused during the preprotection phase before entering the CCA. The study of Leal et al7 showed no contralateral hemispheric infarcts in CASfr patients, while 2 of 11 new DW-MRI lesions detected in CASdp patients were contra-lateral. Gupta et al11 failed to find a significant difference between CASdp and transfemoral CAS with flow reversal in the preprotection phase, indicating the importance of transcervical access to avoid early embolization. The dura-tion of embolic showers did not reveal any differences in the preprotection phase because these showers are very infrequent before manipulating the lesion site.

During stenting and angioplasty, CASdp shows a higher frequency of discrete emboli as well as embolic showers. In many cases, the dynamic flow reversal eliminates emboli-zation during stenting and angioplasty completely, as also reported by Ribo et al14 and Flores et al.8 Although distal protection filters are designed to reduce intraoperative embolization, some studies have found them to be associ-ated with an even higher incidence of microembolization than unprotected stenting.8,21,22 Furthermore, the beneficial effects of the EPD on reducing new DW-MRI lesions are not observed universally.3,23,24

There are several explanations why distal embolic pro-tection filters may not be able to protect the brain. Macroemboli are propelled into the filter and consequently may disintegrate into smaller particles, resulting in a higher apparent microembolic load on TCD.21 Other explanations could be that the deployment of the EPD itself causes more emboli, or the EPD does not appose the artery optimally, or particles smaller than the pore size of the EPD pass unhin-dered to the brain.25,26

In the postprotection phase, after shunt removal and release of the clamps in CEA, retrieval of the EPD, or resto-ration of normal antegrade flow in CAS, no differences could be observed between the different treatment strate-gies. All showed a short burst of emboli, followed by none or infrequent particles.

Although it is a common finding that CASdp is associ-ated with more intraoperative embolization than CEA, direct comparisons may be partially distorted because con-trast injection occurs only in CAS and generates emboli-like signals that are often picked up by automatic detection programs. Because micelles of the contrast agent can gener-ate TCD signals,18 embolic loads may be overestimated for CAS. To avoid this problem, we discarded the signals directly related to contrast injection. Nonetheless, CASdp was still associated with a higher embolization rate. The reliable detection of embolic events in this study was fur-ther confirmed by the high interrater correlations for detect-ing discrete emboli and embolic showers.

As it is unclear whether distal protection filters have a beneficial effect, other cerebral protection methods have been proposed, using an antegrade flow stop or even

Figure 1. (A) Mean number of discrete emboli for each group in each phase. (B) Mean duration of embolic showers for each group in each phase.

Plessers et al.J Endovasc Ther 2016;23:249

TCD Hits During Procedure

TCAR CEA

CAS

TCAR: avoids the arch, offers complete proximal protection. Similar to CEA.

Transcervical Carotid Stent: DW-MRI Lesions

dure. The gastrointestinal bleed was not device related andwas a known complication of concomitant medications.

DW-MRI findings. Thirty-one consecutive subjectsreceived DW-MRI scans (Table IV). Five subjects had newDW-MRI lesions post procedure (16.1%), with a total of 18new DW-MRI lesions across all five patients.

DISCUSSION

Data from multiple randomized studies such asCREST, ICSS, Endarterectomy versus Angioplasty in Pa-tients with Symptomatic Severe Carotid Stenosis (EVA-3S), and Stent-Supported Percutaneous Angioplasty of theCarotid Artery versus Endarterectomy (SPACE) show thatCAS with transfemoral access and the use of distal filters arelimited by both technology and the technical skill requiredof interventionists. The ICSS DW-MRI substudy saw 231symptomatic patients (124 CAS and 107 CEA) undergoDW-MRI pre- and postprocedure.11 Of the CAS patients,50% had at least one new ischemic brain lesion posttreat-ment, compared with just 17% of the CEA patients (P !.0001). The new ischemic brain lesion rate in the CAS armwas highest (73% of patients) in centers with a policy ofusing embolic protection devices, and only distal filter-typedevices were used in ICSS. The review of carotid revascu-larization literature presented by Schaudigel confirms thistrend, with DW-MRI rates of 37% and 10% for CAS andCEA, respectively (P ! .01).8 Of note, the incidence ofnew ischemic brain lesions in the contralateral hemispherewas markedly different between CEA (0.01%) and tradi-tional CAS (14.5%; P ! .01), suggesting embolization intothe contralateral carotid artery stemming from guidewireand catheter manipulation in the aortic arch. By similarlogic, a large proportion of ipsilateral lesions are also likelydue to aortic arch and proximal CCA manipulation inher-ent to the transfemoral access route.

Transfemoral CAS with flow reversal is a method de-veloped by Juan Parodi as an alternative to the use of distalprotection devices. Parodi et al reported that their systemdid not consistently overcome external carotid artery(ECA) to antegrade ICA flow with CCA occlusion aloneand thus incorporated an ECA occlusion element to ensurereversal of flow in the ICA.9 While novel in its approach,

this method still requires unprotected delivery of a cathetersystem from the femoral artery to the CCA and a balloonocclusion device in the ECA, thus creating a potential forvascular trauma and embolic consequence. Parodi et al alsoreported a significant reduction in flow when a stent de-ployment device was introduced into the balloon sheath,coinciding with one of highest-risk moments for embolicdebris generation. Many users of the Parodi system reportadding a syringe aspiration step, as recommended in themanufacturer’s Instructions for Use,12 during any directinteraction with the lesion.

Chang et al13 and Criado et al14 developed a derivativetechnique that combines carotid flow reversal and directaccess of the CCA. This transcervical approach avoids theembolic risk of traversing the aortic arch and supra-aorticvasculature, especially desirable in patients with severe ca-rotid tortuosity and difficult aortic arch anatomy. Severalsingle-center clinical series suggest that transcervical accesswith flow reversal is an effective approach, demonstratingstroke and death rates similar to CEA,15-17 and transcranialDoppler (TCD) measurements showing a cross-clamp-likeabsence of microembolic signals.18

The system studied in this report evolves these flowreversal concepts further. The Chang and Criado approachrequires flow to traverse from artery to vein through thehigh-resistance sidearm connectors of arterial and venoussheaths, which limit the rate of reverse flow. The design ofthe MICHI Neuroprotection System offers a lower resis-tance shunt between arterial and venous circulations, withthe ability to switch between a low, baseline reverse flowrate to a higher flow rate. This higher flow rate obviates theneed to occlude the ECA and may also reduce or eliminatethe need for an active aspiration step. The flow stop andhigh-/low-flow push buttons enables the interventionist tobalance patient tolerance needs with optimal neuroprotec-tion during periods of the procedure that are at highest riskfor liberation of embolic debris (eg, angiography, angio-plasty, stent placement).

This initial experience with the MICHI Neuroprotec-tion System has enabled refinement of patient selection andprocedural techniques for the FAST-CAS procedure. Thecontribution of the highly calcified carotid artery towardone of the failed arterial sheath insertion cases highlightsthe importance of prescreening the common carotid arteryfor suitability of direct cervical access. The procedural ma-neuvers developed to address transient intolerance, espe-cially important in patients with contralateral carotid occlu-sions, highlight the importance of device preparation andthe benefits of FAST-CAS as a relatively short procedure(the mean procedure time from the start of cut down tofinal closure of the arteriotomy was 36 minutes [range, 14minutes to 1 hour 17 minutes]). Switching from high tolow reverse flow, pressing the flow stop button, or un-clamping the CCA and restoring antegrade flow are addi-tional intolerance management strategies. In addition, thetwo cases that converted to CAS with a distal filter demon-strate the ability of the FAST-CAS procedure to safelyconvert to filter-protected transcervical CAS. Converting

Table IV. DW-MRI results (percentage of mITTpatients)

DW-MRI parameters All (n " 31)a

Number of subjects with DW-MRI lesion(s)pre- and postprocedure 1 (3.2%)

Number of subjects with new DW-MRI lesion(s)postprocedure 5 (16.1%)

Total number of new DW-MRI lesion(s)postprocedure 18

Number of new DW-MRI lesion(s) per subjectpostprocedure (min, max) 3.6 (2, 9)

DW-MRI, Diffusion-weighted magnetic resonance imaging; mITT, modi-fied intent to treat.aIncludes all subjects with DW-MRI data.

JOURNAL OF VASCULAR SURGERYNovember 20111322 Pinter et al

Pinter et al. J Vasc Surg 2011;54:1317

cance was defined as two-sided P ! .05. Statistical analysiswas conducted using SPSS 15.0 software (SPSS Inc, Chi-cago, Ill).

We used binary regression models to compare MRIoutcome measures between treatment groups. Interactionsbetween the effect of treatment on the primary outcomemeasure and selected variables (age, sex, operator, type ofstent used, symptomatic status) were investigated and ad-justed for any significant imbalances in baseline character-istics, if necessary.

RESULTS

Patient enrollment. Between April 2008 and June2009, 64 consecutive patients were diagnosed with signif-icant carotid stenosis by ultrasound imaging, and accordingto the inclusion and exclusion criteria, 64 (58 men, 6women) patients, with a mean age of 72.04 (SD, 10.97)years, were enrolled. The procedures were done in twoseparate periods. During the first part of the study, 31patients underwent transcervical carotid stenting. Duringthe second part of the study, 33 patients underwent trans-femoral CAS with distal filter protection.

Patient population. Comorbid conditions are sum-marized in Table I. The two groups did not differ signifi-cantly in demographics, symptomatic status, degree of ste-nosis, and contralateral disease.

Procedural results. We used 45 Wallstents (BostonScientific, Natick, Mass) and 19 Protégé Rx (ev3 Endovas-cular), without reaching a significant difference in the dis-tribution of the types of stent (P " .647). Stent selectionwas determined by lesion characteristics and surgeon pref-erence. A closed-cell design was used whenever possibleand an open-cell one when size discrepancies betweencommon and internal carotid arteries or tortuosities werefound. Predilatation was performed in three patients in thetranscervical group and in two in the transfemoral group(P " .694), using 3- to 4-mm diameter # 2-cm-longballoons inflated to 10 atm.

All procedures were technically successful without($30%) residual stenosis. Mean surgical time was 46 (SD,5.05) minutes in the transcervical group and 52 (SD,10.14) minutes in the transfemoral group, which was notsignificantly different (P " .324). Intolerance to carotidflow reversal was not detected in any patient. After stenting,there were no changes in the stroke scale in any patient ineither group. No strokes or transient ischemic attacks oc-curred. There were no complications related to access sitein either group.

Neurologic evaluation and DW-MRI studies.DW-MRI studies were done in all patients. Mean time fromthe preoperative DW-MRI study and surgical procedurewas 13.5 (SD, 2.4) hours in the transcervical group and11.6 (SD, 2.1) hours in the transfemoral group, withoutsignificant differences between groups (P " .564). Thedelay between procedures and the postoperative DW-MRIstudy was 21.3 (SD, 1.5) hours in the transcervical groupand 20.4 (SD, 2.1) hours in transfemoral group (P "

.354). Results from DW-MRI evaluation are summarizedin Table II.

New postprocedural DWI-MRI–detected cerebralischemic lesions were found in four patients (12.9%) in thetranscervical group. These four patients developed one(two patients), two (one patient), and five (one patient)ischemic lesions, respectively. All lesions were subcortical,

Table I. Comorbid conditions

VariableaTranscervical

(n " 31)Transfemoral

(n " 33) P

Age, mean (SD) years 68.1 (10.7) 67.2 (10.01) .869Sex .346

Male 27 (87.09) 31 (93.94)Female 4 (12.91) 2 (6.06)

Octogenarians 1 (3.23) 1 (3.03) .964Hypertension 24 (77.41) 20 (60.61) .146Diabetes mellitus 11 (35.48) 18 (54.55) .125Hypercholesterolemia 17 (54.84) 15 (45.45) .453Previous myocardial

infarction 7 (22.58) 4 (12.13) .267Current smokers 9 (29.03) 15 (45.45) .689Peripheral arterial

disease 5 (16.13) 4 (12.13) .644Presenting symptoms 21 (67.64) 23 (69.69) .869

Transient ischemicattack 13 (41.93) 15 (45.45) .776

Major stroke 8 (25.81) 8 (24.25) .885Asymptomatic 10 (32.26) 10 (30.03) .886Significant

contralateral ICAdisease 5 (16.13) 3 (9.68) .394

Pre-op Rankin, mean(SD) score 0.6605 (1.14) 0.6745 (1.04) .305

Carotid plaquemorphologyb

Type 1 2 (6.45) 3 (9.68) .694Type 2 9 (29.03) 11 (35.49) .711Type 3 9 (29.03) 8 (24.25) .306Type 4 10 (32.26) 11 (35.49) .927Type 5 1 (3.23) 0 (0) .972

ICA, Internal carotid artery; SD, standard deviation.aData are shown as number (%), unless stated otherwise.bMorphology was assessed according to echolucency criteria. Type 1: dom-inantly echolucent; type 2: substantially echolucent with small areas ofechogenicity; type 3: dominantly echogenic with small areas of echolucency;type 4: uniformly echogenic; and type 5: not classified owing to acousticshadowing artifact.

Table II. Results from diffusion-weighted magneticresonance imaging (DW-MRI) evaluation

Variable

Transcervical(n " 31)No. (%)

Transfemoral(n " 33)No. (%) P

Patients with newlesions

4 (12.90) 11 (33.33) .03

No. of new lesions 4 13 .02Localization of new

lesionsIpsilateral 4 11 .03Contralateral 0 2 .16

JOURNAL OF VASCULAR SURGERYVolume 56, Number 6 Leal et al 1587

Leal et al. J Vasc Surg 2012;56:1585

The PROOF Study DW-MRI Hits Similar to CEA

1 J Am Coll Cardiol. 2012 Jan 19. [Epub ahead of print]

2 Lancet Neurol. 2010 Apr;9(4):353-62

3 Alpaslan, Wintermark, Pinter, Macdonald, Ruedy, Kolvenbach. TransCarotid Artery Revascularization with Flow Reversal: The PROOF Study. J Endovasc Ther. 2016. (In Press)

Study Procedure Embolic Protection Patients New Ipsilateral DWI Lesions

ICSS2 CEA Clamp, backbleed 107 17%

PROOF3 TCAR Proximal clamp, reversed flow 56 18%

PROFI1 Transfemoral CAS

Proximal occlusion (MoMA) 31 45%

ICSS2 Transfemoral CAS

Distal filter (various) 51 73%

PROFI1 Transfemoral CAS

Distal filter (Emboshield) 31 87%

TCAR Clinical Data

Study Sample Size

Purpose Study Population

Primary Endpoint NPS Config

PROOF 75 First in Human Mostly HSR S/D/MI at 30 Days Gen 1

PROOF DW-MRI 56 Sub-study in PROOF Mostly HSR Rate of New White Lesions

Gen 1

TESLA 58 European post-market study of NPS (all stents)

79% HSR 21% SSR

Stroke in hospital Gen 1

ROADSTER 1 141 Pivotal trial for NPS (all stents) HSR S/D/MI at 30 Days Gen 1

ROADSTER 1 Continued Access

78 Continued enrollment during FDA review of R1

HSR S/D/MI at 30 Days Gen 1.5

ROADSTER 1 Stent Substudy

52 FDA Approval of ENROUTE Stent using Cordis Precise

HSR Procedural Success at 30 Days

Gen 1

ROADSTER 1 One Year Follow-Up

112 Durability of stenting with TCAR HSR Ipsilateral Stroke at 1 year

Gen 1/Gen 1.5

ROADSTER 2* Minimum of 600

Post approval study for FDA following stent PMA approval

HSR Procedural Success at 30 Days

Gen 2

ROADSTER I: US Pivotal Trial TCAR in Patients at High Risk for CEA

Kwolek et al. J Vasc Surg 2015;62:1227

the outcomes in CREST in patients at standard surgicalrisk: all stroke was 2.3% and stroke/death was 2.6% inthe CEA limb and all stroke was 4.1% and stroke/deathwas 4.8% in the TF filter-protected CAS limb. Periproce-dural stroke in the CREST study was accompanied by infe-rior functional status and demonstrably poor late survival.15

A systematic review of transcarotid CAS reported a 1.1%stroke rate.16 However this review comprised 12 studiesthat were retrospectively reviewed and self-audited in themain, with a mix of baseline risk (to include standard riskpatients) and differences in both end point assessment(in-hospital vs 30-day outcomes) and in protection meth-odology (distal filter or flow reversal). Accordingly, thestroke rate reported in this collective review may beunder-reported.

Current limitations of the field. Although the designof the ENROUTE Transcarotid NPS is surgically inspired,demonstrable advantages of this hybrid minimally invasivesystem over CEA extend to the issue of CNI and oropha-ryngeal dysfunction after CEA. In the CREST CEAcohort, the rate of procedural CNIs was 4.7%, and 2%were persistent at 6 months; 80% of these comprised motor

deficits. In ROADSTER, the CNI rate was 0.7%, with thesingle event being transient. Unlike CEA, the only “at risk”cranial nerve is the vagus and thereby the recurrent laryn-geal. The incidence and severity of CNI is thus expectedto be less for the ENROUTE Transcarotid NPS than forCEA. This advantage is amplified in circumstances of recur-rent stenosis after CEA.17 The CNI rate for CEA was 6% in1645 patients in the Carotid Stenting Trialists’ Collabo-ration (CSTC), which was a preplanned meta-analysis ofindividual patient data from three European randomizedtrials of TF filter-protected CAS vs CEA in symptomaticpatients.18

In CREST, CEA was associated with a significantlyhigher MI rate than TF filter-protected CAS (2.3% vs1.1%; P ¼ .03), and this component part of the compos-ite end point (stroke, death, MI) had important prog-nostic implications compared with minor stroke withregard to 4-year mortality (major stroke and MI werecomparable in effect on 4-year mortality).19 In ROAD-STER, the MI rate was 0.7%. The rate was 0% in thosepatients being treated under local anesthesia, suggestingthat transcarotid stenting with dynamic flow reversalcan effectively match TF CAS with respect to MI whilematching CEA with respect to incidence of stroke anddeath.

Local complications requiring a return to the operatingroom were significantly more frequent after CEA thanafter TF filter-protected CAS in CREST (3.7% vs 1.1%;P ¼ .0001) and in the CSTC (2.1% vs 0.8% P ¼ .0016).Rates of arterial dissection vary across contemporaneousstudies of CAS and embolic protection devices (from0% to 3.28%).20,21 The rate of serious arterial dissection(those requiring treatment) at the arterial access site inROADSTER was 2.1% (3 of 141). Furthermore, dissectionrates in other CAS trials reflect dissection at the index ICAlesion rather than at the access site (self-limiting femoral ar-tery dissection is likely to be under-reported in the absenceof routine postprocedure angiography at the access site).The rate of serious wound hematoma in ROADSTERwas 0.7% (1 of 141). This compares favorably with theserious groin hematoma rate of 0.8% for proximal protec-tion with the Gore Flow Reversal System (W. L. Goreand Associates, Flagstaff, Ariz).22 Wound/groin hematomarates are rarely reported separately in other contempora-neous CAS and embolic protection device studies; oneother study reported a discrete hematoma rate of 2.1%.21

Mean procedure time (skin-to-skin) for this novel tech-nique was 73.6 minutes (95% CI, 68.9-78.2 minutes) evenwith study-mandated serial activated clotting time mea-surements throughout the procedure. The mean proce-dural times for CEA and TF CAS in CREST were 171 655 minutes and 69 6 31 minutes, respectively.23 Thefact that procedural times compare favorably with TFCAS and CEA likely reflects arch avoidance and limited tis-sue dissection. In ROADSTER, 36% of patients had hostileneck anatomy; thus, the small, supraclavicular incisionrequired for the ENROUTE Transcarotid NPS cannot be

Table VII. Procedural parameters

VariablesNo. (%) or mean 6 SD(min, max) (N ¼ 141)

Anesthetic modalityLocal anesthesia 74 (53)General anesthesia 67 (47)

Flow reversal time, minutesTime on high-flow 12.9 6 8.6

ToleranceTo flow reversal 141 (100)To high-flow 140 (99)

Procedure time: CCA cutdown toskin closure, minutes

73.6 6 30.77 (68.2, 78.2)

Acute device success 140 (99)Technical success 140 (99)Procedural success 135 (96)

CCA, Common carotid artery; SD, standard deviation.

Table VIII. Hierarchical presentation of the majoradverse event (MAE) rate for the intention to treat (ITT)population

Parameters and statisticsITT population(N ¼ 141)

Patients who experienced an MAE,a No. (%) 5 (3.5)Exact binomial, 95% CI 1.16-8.08P value .0047Events #30 days of the index procedure

Patients who died, No. (%) 2 (1.4)Patients who had a stroke, No (%) 2 (1.4)Patients who had an MI, No. (%) 1 (0.7)

CI, Confidence interval; MI, myocardial infarction.aDefined as stroke, death, myocardial infarction.

JOURNAL OF VASCULAR SURGERY1232 Kwolek et al November 2015

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the outcomes in CREST in patients at standard surgicalrisk: all stroke was 2.3% and stroke/death was 2.6% inthe CEA limb and all stroke was 4.1% and stroke/deathwas 4.8% in the TF filter-protected CAS limb. Periproce-dural stroke in the CREST study was accompanied by infe-rior functional status and demonstrably poor late survival.15

A systematic review of transcarotid CAS reported a 1.1%stroke rate.16 However this review comprised 12 studiesthat were retrospectively reviewed and self-audited in themain, with a mix of baseline risk (to include standard riskpatients) and differences in both end point assessment(in-hospital vs 30-day outcomes) and in protection meth-odology (distal filter or flow reversal). Accordingly, thestroke rate reported in this collective review may beunder-reported.

Current limitations of the field. Although the designof the ENROUTE Transcarotid NPS is surgically inspired,demonstrable advantages of this hybrid minimally invasivesystem over CEA extend to the issue of CNI and oropha-ryngeal dysfunction after CEA. In the CREST CEAcohort, the rate of procedural CNIs was 4.7%, and 2%were persistent at 6 months; 80% of these comprised motor

deficits. In ROADSTER, the CNI rate was 0.7%, with thesingle event being transient. Unlike CEA, the only “at risk”cranial nerve is the vagus and thereby the recurrent laryn-geal. The incidence and severity of CNI is thus expectedto be less for the ENROUTE Transcarotid NPS than forCEA. This advantage is amplified in circumstances of recur-rent stenosis after CEA.17 The CNI rate for CEA was 6% in1645 patients in the Carotid Stenting Trialists’ Collabo-ration (CSTC), which was a preplanned meta-analysis ofindividual patient data from three European randomizedtrials of TF filter-protected CAS vs CEA in symptomaticpatients.18

In CREST, CEA was associated with a significantlyhigher MI rate than TF filter-protected CAS (2.3% vs1.1%; P ¼ .03), and this component part of the compos-ite end point (stroke, death, MI) had important prog-nostic implications compared with minor stroke withregard to 4-year mortality (major stroke and MI werecomparable in effect on 4-year mortality).19 In ROAD-STER, the MI rate was 0.7%. The rate was 0% in thosepatients being treated under local anesthesia, suggestingthat transcarotid stenting with dynamic flow reversalcan effectively match TF CAS with respect to MI whilematching CEA with respect to incidence of stroke anddeath.

Local complications requiring a return to the operatingroom were significantly more frequent after CEA thanafter TF filter-protected CAS in CREST (3.7% vs 1.1%;P ¼ .0001) and in the CSTC (2.1% vs 0.8% P ¼ .0016).Rates of arterial dissection vary across contemporaneousstudies of CAS and embolic protection devices (from0% to 3.28%).20,21 The rate of serious arterial dissection(those requiring treatment) at the arterial access site inROADSTER was 2.1% (3 of 141). Furthermore, dissectionrates in other CAS trials reflect dissection at the index ICAlesion rather than at the access site (self-limiting femoral ar-tery dissection is likely to be under-reported in the absenceof routine postprocedure angiography at the access site).The rate of serious wound hematoma in ROADSTERwas 0.7% (1 of 141). This compares favorably with theserious groin hematoma rate of 0.8% for proximal protec-tion with the Gore Flow Reversal System (W. L. Goreand Associates, Flagstaff, Ariz).22 Wound/groin hematomarates are rarely reported separately in other contempora-neous CAS and embolic protection device studies; oneother study reported a discrete hematoma rate of 2.1%.21

Mean procedure time (skin-to-skin) for this novel tech-nique was 73.6 minutes (95% CI, 68.9-78.2 minutes) evenwith study-mandated serial activated clotting time mea-surements throughout the procedure. The mean proce-dural times for CEA and TF CAS in CREST were 171 655 minutes and 69 6 31 minutes, respectively.23 Thefact that procedural times compare favorably with TFCAS and CEA likely reflects arch avoidance and limited tis-sue dissection. In ROADSTER, 36% of patients had hostileneck anatomy; thus, the small, supraclavicular incisionrequired for the ENROUTE Transcarotid NPS cannot be

Table VII. Procedural parameters

VariablesNo. (%) or mean 6 SD(min, max) (N ¼ 141)

Anesthetic modalityLocal anesthesia 74 (53)General anesthesia 67 (47)

Flow reversal time, minutesTime on high-flow 12.9 6 8.6

ToleranceTo flow reversal 141 (100)To high-flow 140 (99)

Procedure time: CCA cutdown toskin closure, minutes

73.6 6 30.77 (68.2, 78.2)

Acute device success 140 (99)Technical success 140 (99)Procedural success 135 (96)

CCA, Common carotid artery; SD, standard deviation.

Table VIII. Hierarchical presentation of the majoradverse event (MAE) rate for the intention to treat (ITT)population

Parameters and statisticsITT population(N ¼ 141)

Patients who experienced an MAE,a No. (%) 5 (3.5)Exact binomial, 95% CI 1.16-8.08P value .0047Events #30 days of the index procedure

Patients who died, No. (%) 2 (1.4)Patients who had a stroke, No (%) 2 (1.4)Patients who had an MI, No. (%) 1 (0.7)

CI, Confidence interval; MI, myocardial infarction.aDefined as stroke, death, myocardial infarction.

JOURNAL OF VASCULAR SURGERY1232 Kwolek et al November 2015

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variable was each SF-36 subscale at 2 weeks, 1 month,and 1 year of follow-up. In addition to periproceduralCNI, variables included in the models were baselineSF-36 scores, age, sex, symptomatic status, follow-uptime, and the interaction between periprocedural CNIand follow-up time, where the time variable was set asboth random and fixed effects. The random effectsgrowth curve model was implemented using the PROCMIXED procedure in SAS 9.3 software (SAS InstituteInc, Cary, NC).

To assess the effect of periprocedural CNI on eachdisease-specific Likert scale, we treated each Likert scaleas an ordinal outcome and used repeated ordinal logisticregression to analyze the data. Similar to the growth curvemodels, this method uses all available data under theassumption that any missing data are missing at random.In addition to periprocedural CNI, variables included inthe models were the baseline value for each Likert scale,age, sex, symptomatic status, follow-up time, and the inter-action between periprocedural CNI and follow-up time.The time variable was set as both random and fixed effects.The results of this analysis are described in terms of oddsratios (with confidence intervals) that represented theadjusted odds of a one-level increase in severity for therespective scales. The analysis was done using the PROCGLIMMIX procedure in SAS 9.3 software.

RESULTS

In CREST, CNI occurred in 53 of 1151 patients(4.6%) randomized to CEA who underwent the procedure#30 days of randomization. The distribution of injuries isreported in Table II. Injuries that affected the ability toswallow or vocalize were most common, followed by injuryto the marginal mandibular branch of the facial nerve andthe hypoglossal nerve. One patient had tongue deviationand hoarseness/dysphagia but was classified as a CN XIIinjury to simplify the analysis.

Status of the patient’s injuries was also assessed at the1-month and 12-month follow-up visits, and these resultsare also reported in Table II. Thirty-four percent (18 of53) of the injuries had resolved #1 month of operation,whereas at 12 months, 80.8% (42 of 52) were no longerpresent in the surviving patients. One patient died beforethe 1-year follow-up visit. No hypoglossal nerve injuries

were permanent, but >10% of injuries diagnosed as vagusor glossopharyngeal nerves were permanent.

The analysis excluded five patients because two under-went surgery >30 days after the randomization windowand three were crossovers from the CAS group. Three in-juries were to CN XII and two were to CN X. Four werestill present at the 30-day follow-up, but all five hadresolved by 12 months after the operation.

Baseline demographic characteristics in patients whoexperienced CNI were compared with those withoutCNI to identify factors that might predict a higher likeli-hood of CNI. No significant differences were noted be-tween the two groups with respect to age, sex, presenceof symptoms, smoking status, and whether the patientshad a history of diabetes mellitus, hypertension, dyslipide-mia, or coronary disease (Table III).

Details of operative variables, including the side ofoperation, anesthetic type, operative time, reoperation forhematoma, and use of a patch or shunt, were alsocompared between the groups with and without CNI(Table IV). CNI was significantly higher in patients oper-ated on under general anesthesia (5.0% vs 0.9%; P ¼ .05)compared with those operated on under local anesthesia.Shunts were used significantly more frequently in the gen-eral anesthesia group (59.8%) than in the local anesthesiagroup (31.2%; P < .0001). No other differences weredetected that increased the probability of CNI.

The results of the comparison between the groups withand without CNI on the SF-36 surveys are shown in Fig 1.No significant differences were noted in any of the SF-36subscales between the groups with and without CNI atany time. Fig 2 shows the results of the comparison of re-sponses to the Likert scales at the three intervals after thesurgical procedures. The group with CNI demonstratedgreater difficulty with eating/swallowing at 2 weeks and1 month after the surgical procedure compared with thegroup without CNI (P < .001). At 1 year, there were nosignificant differences on any of the Likert scales betweenthe CNI and no CNI group, although there was still a

Table II. Resolution of cranial nerve injuries (CNIs)over time

Type of injury

Presentimmediately

post-op, No. (%)

Present at1 month,No. (%)

Present at12 months,No. (%)

Hypoglossal (XII) 13 (24.5) 6 (11.3) 0 (0)a,bFacial (VII) 16 (30.2) 10 (18.9) 3 (5.8)Dysphagia/hoarseness (IX, X)

22 (41.5) 18 (33.9) 6 (11.5)c

Horner syndrome 2 (3.8) 1 (1.9) 1 (1.9)Any CNI 53 (100) 35 (66) 10 (19.2)a

aOne patient was diagnosed with lung cancer 1 month postprocedure anddied 6 months postprocedure.bOne patient with tongue deviation and hoarseness/dysphagia was classifiedas having CN XII injury.cOne patient had unknown status at 12 months; however, when queriedlater on, the patient did not recall experiencing any hoarseness and wasclassified as resolved.

Table I. Cranial nerve injury (CNI) definitions

CN Symptoms

XII (hypoglossal) Ipsilateral tongue deviationVII (facial) Ipsilateral facial droop

Inability to depress ipsilateralcorner of lip

X/IX (vagus/glossopharyngeal) Dysphagia, hoarsenessIpsilateral vocal cord paralysis

on laryngoscopyaHorner syndrome Ipsilateral ptosis, miosis

aNot systematically performed.

JOURNAL OF VASCULAR SURGERY1210 Hye et al May 2015

Cranial Nerve Injuries In the CREST Trial

Hye et al. J Vasc Surg 2015;61:1208

CNI: 5.3% overall

Roadster 1: Cranial nerve injury=0.7%, present at 6 months=0

ROADSTER: Procedure Information

Parameter ROADSTER 1 n=219

ROADSTER 2 n=486

ROADSTER 1 Operators 100% 17.9% New TCAR Operators 76.2% 82.1%

Enrollment by New Operators 65.3% 70.0% Skin-to-Skin Time (median) 70 mins 69 mins Reverse Flow/Clamp Time (median) 9 mins 9 mins

Tolerance to High Flow 98.6% 98.6% Tolerance to Low Flow 100% 100%

Fluoro Time (median) N/R 4.3 mins Contrast Usage (median) 62 cc 30 cc

ROADSTER 2: Clinical Outcomes

ROADSTER

1 ROADSTER

2 n= 203 n= 438

Stroke/Death/MI 6 3.0% 6 1.4%Stroke 1 0.5% 3 0.7%Death 2 1.0% 1* 0.2%MI 3 1.5% 2 0.5%

Stroke/Death 3 1.5% 4 0.9%Neurological Death 0 0.0% 0 0.0%

Patients Treated Per Protocol

*One patient expired ~2 weeks post-procedure due to ruptured AAA.

ROADSTER Outcomes by Symptom Status

ROADSTER 1 ROADSTER 2 n=157 n=325Stroke/Death/MI 4 2.5% 5 1.5%

Stroke 1 0.6% 2 0.6%Death 1 0.6% 1 0.3%MI 2 1.3% 2 0.6%

Stroke/Death 2 1.3% 3 0.9%

Asymptomatic Patients – Per Protocol

ROADSTER 1ROADSTER 2 n=46 n=113Stroke/Death/MI 1 2.2% 1 0.9%

Stroke 0 0.0% 1 0.9%Death 1 2.2% 0 0.0%MI 0 0.0% 0 0.0%

Stroke/Death 1 2.2% 1 0.9%

Symptomatic Patients – Per Protocol

Patient selection CCA must be clean Minimum 5cm clavicle to bifurcation Exclude intracranial occlusive disease

TCAR: Technical Aspects

§  Extend neck §  Ultrasound prior to incision. Check CCA quality and depth. §  Transverse-between sternal and clavicular heads of SCM. §  Don’t pull up on purse string suture. §  Pre-mark the needle and wire (so you know the distance). §  Single wall puncture with micropuncture. §  Use external carotid as needed. §  Stop flow for angiogram. §  Continue reversed flow after stent placement.

Transcervical Carotid Stenting Conclusion

§  Transcervical approach -  Arch avoidance. -  Protect before crossing. -  Proximal clamp/reversed flow=more complete

protection. -  Mounting clinical data.