Need for adjunctive procedures following cyanoacrylate closure of incompetent great,small and accessory saphenous veins without the use of postprocedure compression: Three-month data from a postmarket evaluation of the VenaSeal System (the WAVES Study)

Abstract

Purpose

Studies examining cyanoacrylate closure of saphenous veins with the VenaSeal™ System have not allowed concomitant procedures for tributaries at the time of the index procedure. Outside of clinical trials, however, concomitant procedures are frequently performed in conjunction with endovenous ablation. We report on the frequency of need for saphenous tributary treatment three months after cyanoacrylate closure of the treatment of great saphenous vein, small saphenous vein, and/or accessory saphenous vein.

Methods

Fifty subjects with symptomatic great saphenous vein, small saphenous vein, and/or accessory saphenous vein incompetence were treated with no postprocedure compression stockings. Concomitant procedures were not allowed. Treating physicians predicted the type and nature of any concomitant procedures that they would usually perform at the time of ablation, if not limited by the constraints of the study. Evaluations were performed at one week, one and three months and included duplex ultrasound, numeric pain rating scale, revised venous clinical severity score, the Aberdeen Varicose Vein Questionnaire, and time to return to work and normal activities. At the three-month visit, the need for and type of adjunctive procedures were recorded.

Results

Complete closure at three months was achieved in 70 (99%) of the treated veins (48 great saphenous veins, 14 accessory saphenous veins, eight small saphenous veins). Revised venous clinical severity score improved from 6.4 ± 2.2 to 1.8 ± 1.5 (P < .001) and Aberdeen Varicose Vein Questionnaire from 17.3 ± 7.9 to 6.5 ± 7.2 (P < .0001). Sixty-six percent of patients underwent tributary treatment at three months. The percentage of patients who required adjunctive treatments at three months was lower than had been predicted by the treating physicians (65% versus 96%, p=.0002).

Conclusions

Closure rates were high in the absence of the use of compression stockings or side branch treatment. Improvement in quality of life was significant, and the need for and extent of concomitant procedures was significantly less than had been predicted by the treating physicians.

Keywords

Chronic venous insufficiency endovenous technique great saphenous vein small saphenous vein varicose veins

Introduction

Prior to the advent of endovenous thermal ablation (ETA), endovenous laser ablation, and radiofrequency ablation (RFA), most patients with saphenous vein incompetence were treated with high ligation and stripping, with varicose vein tributaries commonly removed at the same time with avulsion phlebectomy. In the United States, most venous procedures are now performed in an outpatient setting with ETA.¹ ETA procedures require tumescent anesthesia, with multiple needle sticks which can cause bruising and discomfort. Newer technologies have been developed that do not require tumescent anesthesia to ablate incompetent saphenous segments.

Cyanoacrylate closure (CAC) of saphenous veins received FDA approval in 2015.² Marketed by Medtronic as the VenaSeal™ Closure System, three Medtronic clinical trials preceded the present study. The mechanism of action is unique in that CAC coapts the vein wall using adhesive and external compression, causing a nonthrombotic obliteration of the vein lumen.³ A 38-patient first-in-man feasibility study has results reported to three years,^4,5 a multicenter European cohort study (eSCOPE trial) of 70 patients has results reported to one year,⁶ and the pivotal US VeClose trial has been reported to one and two years,^7,8 with three-year results presented on podium and soon to be submitted for publication.⁹ At three years, the VeClose study demonstrated noninferiority of CAC to RFA for duplex-assessed closure rates of the great saphenous vein (GSV): 94.4 and 91.9%, respectively (P = 0.005; noninferiority). The purpose of the Lake Washington Vascular VenaSeal Post-Market Evaluation (abbreviated WAVES) study was to investigate the performance of CAC in a real-world setting in which multiple incompetent saphenous trunks were treated in the same setting, and compression stockings were not used postoperatively. This trial differed from previous studies, in that the inclusion criteria for this study were liberalized, and veins up to 20 mm in diameter could be treated. One-month results have been previously published and showed 100% closure rates at that time.¹⁰ Three-month results of the WAVES trial are presented herein.

Methods

Study design

WAVES is a single-center, multi-investigator, single-arm prospective study investigating the use of CAC in a cohort of subjects with symptomatic venous reflux disease in the GSV, small saphenous vein (SSV), and/or accessory saphenous vein (ASV). Institutional review board approval was obtained, and the study was registered on ClinicalTrials.gov (NCT02585726). Between October and December 2015, 50 subjects were enrolled and treated.

Study subjects

Patients aged 18–80 years with symptomatic chronic venous disease, CEAP (clinical, etiologic, anatomic, pathophysiologic) clinical classification C2–C5, and incompetence of the GSV, SSV, and/or ASV were enrolled in the trial. To qualify for treatment, veins targeted for treatment needed to demonstrate at least 0.5 s of reflux, measure at least 4 mm but no more than 20 mm in diameter and contain a refluxing segment of at least 10 cm in length. Vein diameters were measured in standing position, and the largest in-fascia truncal vein diameter in the segment intended for treatment (excluding the saphenofemoral and/or saphenopopliteal junction or a focal dilatation such as a valve site) was recorded as the target vein (TV) diameter. The treatment of multiple saphenous trunks in a single limb was allowed if size and reflux criteria were met. Treatment of veins outside the saphenous fascia and below knee saphenous segments was allowed. Subjects were excluded if they were pregnant (women of child-bearing potential underwent preprocedure pregnancy tests) or breastfeeding or had a history of previous deep venous thrombosis (DVT). A current history of active superficial thrombophlebitis in the limb to be treated, prior treatment of TVs, or veins too tortuous to allow passage of the CAC device were also exclusions.

Informed consent was obtained after verification of eligibility. The baseline visit included a focused physical examination, collection of CEAP, revised Venous Clinical Severity Scores (rVCSS),¹¹ Aberdeen Varicose Vein Questionnaires (AVVQ),¹² EuroQOL Visual Analogue Scale (EQ VAS),¹³ Numerical Rating Scale (NRS),¹⁴ and a deep and superficial duplex ultrasound (DUS) of the target limb. The DUS was performed in the standing position with standard protocols, and reflux was defined as >500 ms of retrograde flow with Valsalva and/or distal compression and release.

Treatment

At the time of the baseline assessment, the treating physician determined which vein(s) would be treated with CAC and deemed which vein would be designated as the primary target vein (PTV). No concomitant procedures such as microphlebectomy or sclerotherapy were allowed. Prior to treatment, the investigator was required to make a prediction of whether the subject would require adjuvant therapy, what kind of treatment would be necessary (microphlebectomy versus sclerotherapy), and how extensive the treatment would be (number of incisions or injection sites). In the investigators’ practice, microphlebectomy is typically performed on larger tributaries and sclerotherapy on smaller tributaries. A procedure score was developed for the purposes of this trial to reflect the more invasive nature of microphlebectomy compared to sclerotherapy. The procedure score was defined as the sum of the number of predicted or actual phlebectomy incisions × 2 and the number of predicted or actual sclerotherapy injection sites.

The technique used for this study was per manufacturer’s instructions for use and has been previously described in the one-month paper.^10,15

During the procedure, data collected included the identification of PTV (defined as the GSV if the GSV was treated—or if the GSV was not treated, as specified by the treating physician) and other treated veins, the length of each segment treated, the location of each segment, the total amount of adhesive delivered, procedure time, and any technical or device problems. Verification of vein closure was made for each TV segment with DUS. All subjects ambulated immediately, and no compression stockings were required after the procedure. Subjects were instructed to ambulate frequently and to return to work or normal activities at their own discretion.

Postprocedure visits

Study subjects returned for evaluation at one week, one month, three months, and one-year postprocedure. At each visit, adverse events (AEs) were collected; a brief examination of the index limb was performed; and rVCSS, AVVQ, EQ VAS, and NRS were collected. A DUS was obtained to rule out DVT and assess vein closure. AEs were graded in severity by the investigators and were deemed to be related to the device or procedure, probably related, possibly related, or not related.

At the three-month visit, the patient completed all study procedures (duplex and physical examination, as well as all patient questionnaires). A determination what if any adjunctive procedures to be performed was then made. Adjunctive procedures could have been indicated for residual symptomatic tributaries, for cosmetic reasons, or both. The patients were at liberty to decline adjunctive procedures, even if they were advised by the treating physician that they would be helpful, although the treating physician had sole discretion in deciding the nature (sclerotherapy, microphlebectomy, or both) and extent of the adjunctive procedures. The number of incisions and the number of injection sites for sclerotherapy, if present, were recorded for each patient that underwent adjunctive procedures.

Statistical methods

The primary study endpoint was complete closure (CC) of the PTV. CC was defined as DUS of the TV showing no areas of patency—as demonstrated by color flow and compression—of more than 5 cm in length at one- and three-month posttreatment. CC of all TV, CEAP, rVCSS, AVVQ, and EQ VAS were tabulated. This is a report of results available at month 3 postprocedure.

Baseline variables are summarized with the use of descriptive statistics. Continuous variables are summarized as the mean, median, standard deviation, and/or minimum and maximum values, as specified. Categorical variables are summarized as counts and percentages. Confidence intervals (CIs) are specified at the 95% level and calculated using the modified Wald method.¹⁶ Linear regression models were created for outcome variables using a stepwise approach with a stepwise algorithm to identify the significant risk factors for selected outcome variables. Statistical significance was assumed when the two-tailed P value was less than .05.

Results

Study subject characteristics

Sixty-one subjects were screened for the WAVES study, and 50 met enrollment criteria. All 50 subjects presented for one-week, one-month, and three-month follow-up visits. Table 1 shows subject demographics and clinical staging. The majority of the subjects were women (70%) and Caucasian (94%). The most frequent presenting CEAP clinical class was class 2 (36%).

Table 1.

Patient demographics and clinical staging.

Characteristic
Gender
Male	15/50 (30%)
Female	35/50 (70%)
Age (mean ± SD, median)	49.5±12.1(51.0)
BMI (mean ± SD, median)	26.9±5.5 (26)
Race
White	46/50 (92%)
Black	2/50 (4%)
Asian	1/50 (2%)
Pacific Islander	1/50 (2%)
Smoking
Current	1/50 (2%)
Former	19/50 (38%)
Never	30/50 (60%)
CEAP clinical class of treated limb
C2	18/50 (36%)
C3	14/50 (28%)
C4a/b	17/50 (34%)
C5	1/50 (2%)

BMI: Body Mass Index; CEAP: Clinical, Etiologic, Anatomic, Pathology; SD: standard deviation.

Table 2 lists the venous segments identified by preoperative DUS and subsequently treated with CAC. The investigators specified the GSV as the PTV in 48 subjects (96%). A single TV was identified in 31 subjects (62%), which was the GSV in all but one case (97%). Among the remaining 19 subjects with more than one TV, 18 (36%) had two TVs, and one (2%) had three TVs.

Table 2.

Veins identified and treated.

	One PTV	Two TV	Three TV	Total
GSV	30	17	1	48
ASV	0	13	1	14
SSV	1	6	1	8

ASV: accessory saphenous vein; GSV: great saphenous vein; PTV: primary target vein; SSV: small saphenous vein; TV: target vein.

Vein closure

A total of 70 TV were successfully treated in the 50 subjects (48 GSVs, 14 ASVs, and eight SSVs). There were no technical or device-related complications during the index procedure. Procedural details and immediate and one-month results have been previously reported in the one-month WAVES publication.⁹ Duplex-assessed CC of the PTVs and all TV immediately at three months and 98.6%, respectively. At three months, CC was achieved in the PTV in 50/50 subjects (95% CI 94.2–100%) and 69/70 TV (95% CI 92.3–100%). GSV and SSV closures were 100% (95% CI 94.0–100% for GSVs, 68.8–100% for SSVs) and ASV closures were 92.9% (95% CI 66.1–99.8% for ASVs). The patient who had recanalization of the ASV had successful closure of her PTV, the GSV, at the three-month visit. The single vein that recanalized was a large ASV (10.8 mm in diameter) that was closed over a length of 8 mm in a patient with a BMI of 39. On duplex imaging, the cyanoacrylate adhesive was still visible on the anterior wall of the previously closed vein, but the posterior wall appeared normal.

Clinical outcome measures

Table 3 summarizes rVCSS, AVVQ, and EQ VAS at baseline and at the one- and three-month visits. Improvement in all three measures was statistically significant between baseline and one month, and baseline and three-month visits (P < .001). The AVVQ showed continued improvement between the one- and three-month visits that was statistically significant (P<.0001).

Table 3.

Clinical outcome measures.

	Baseline	One month	Three months	p-value*
rVCSS (mean ± SD, median)	6.5± 2.4, 6.0	1.8±1.4, 1.0	1.8±1.4, 1.0	<.0001
AVVQ (mean ± SD, median)	17.3±8.8, 16.4	8.9±6.6, 7.5	6.5±7.2, 4.1	<.0001
EQ VAS (mean ± SD, median)	84.4±11.6, 89	88.3±8.7, 90	88.6±10.6, 90	<.0001

AVVQ: Aberdeen varicose vein questionnaire; EQ VAS: EuroQol Visual Analog scale; rVCSS: revised venous clinical severity score.

*p-value of three months to baseline data.

Adjunctive procedures

Prior to the index procedure, the treating physicians estimated that if allowed to perform concomitant procedures, 74% of patients would undergo microphlebectomy, 90% sclerotherapy, and only 4% of patients would undergo no adjunctive procedures. In our practice, patients may undergo both microphlebectomy and sclerotherapy at the same treatment session. Table 4 shows the actual versus predicted need for adjunctive procedures. At three months, 66% of patients underwent adjunctive procedures, significantly fewer than what had been predicted (p=.0002). Only 14% of patients underwent microphlebectomy, considerably less than what had been predicted (p=.0001). The total procedure score of what procedure was performed at three months was significantly less than what had been predicted, with a mean procedure score of 3.9 (± 6.1) at month 3, compared to 17.6 (± 12.7) on the day of the procedure (p<.0001). Three patients had actual procedure scores higher than predicted, one patient was the same as predicted and 46 had actual procedure scores less than predicted.

Table 4.

Actual versus predicted need for adjunctive procedures at three months.

	Predicted	Actual	p-value
Phlebectomy	37 (74%)	7 (14%)	.0001
Sclerotherapy	45 (90%)	33 (66%)	.018
Any procedure	48 (96%)	33 (66%)	.0001

AEs. During the study period there were no serious adverse events. AEs were mild and well tolerated. AEs from the index procedure to the one-month visit have previously been reported. Between the one- and three-month visits, there was one AE-knee bursitis in the treatment limb. This was determined by the treating physician to be unrelated to the procedure.

Of the 33 patients who underwent branch sclerotherapy after the three-month visit, 10 returned to clinic for drainage of trapped coagula in thrombosed treated branches. There were no infections, deep vein thrombosis, or other AEs related to branch treatment—either microphlebectomy or sclerotherapy.

Discussion

The WAVES study demonstrates continued safety and efficacy of CAC at three months as applied in a real-world setting in which the treatment of multiple incompetent venous segments was permitted, larger veins were treated, and subjects did not wear compression stockings postoperatively. Of note, the single ASV that reopened between the one- and three-month visits was large, and a short length of this vein was closed. It is possible that a “longer” closure may be preferable for the procedure, especially in obese patients who have increased venous pressures due to central adiposity.¹⁷

Quality of life (QOL) as measured by the AVVQ continued to show improvement between the one- and three-month visits. As this trial differed from the VeClose trial in that it allowed the treatment of multiple venous segments in one setting, included treatment of the SSV, and did not require the use of compression stockings, these data show that in the mid-term, CAC is safe and efficacious both by objective measures (duplex closure) and by patient assessments.

With the migration of superficial venous procedures from the hospital to the outpatient setting, new paradigms emerged to treat varicose tributaries. Tributaries can either be treated at the same time as truncal ablation (concomitant treatment) or in a staged fashion. There are proponents of both concomitant and staged procedures for addressing venous tributaries, with proponents of staging arguing that many of the tributaries may regress in size and symptoms, making adjunctive treatment unnecessary.^18,19 Proponents of concomitant procedures argue that patients prefer having all of their venous pathology treated in one treatment session and that there are early advantages to concomitant procedures in terms of patient QOL measures.²⁰ This may be more convenient for both the patient and the physician. On the other hand, treating every patient with concomitant branch therapy may be overtreating a number of patients in whom the dilated tributaries would regress if given time and may increase risk of venous thrombotic events.²¹

Like the previous CAC trials, the WAVES protocol did not allow adjunctive tributary treatment at the time of saphenous vein closure to prevent confounding of assessments of pain, QOL, and AEs. All patients, therefore by nature of the protocol underwent staging of any necessary tributary procedures. We were particularly interested to see whether the number and type of adjunctive procedures (sclerotherapy, microphlebectomy, or both) would be greater or lesser at three months than what was predicted by the treating physician on the day of the patient’s index procedure. The mandate that tributary branch treatment be staged allowed us to follow the tributaries longitudinally to see the extent to which they regressed with treatment of the truncal reflux.

In our study, the degree to which branches regressed, and the inability of the investigators to accurately predict need for concomitant procedures was a surprising finding. Our typical practice had been to perform microphlebectomy on larger (greater than 4 mm) tributary branches and foam sclerotherapy for smaller branches (less than 4 mm), typically in a concomitant fashion. Because of this study, our practice pattern has changed, and we now treat a higher percentage of our patients in a staged fashion, particularly when using CAC to treat truncal incompetence. The percentage of patients requiring phlebectomy at three months was lower than reported by other authors,^18–20 although none of these authors performed adjunctive sclerotherapy on their patients, just microphlebectomy. The reason for this difference is not clear. It is possible that our group is more likely to treat tributaries with foam sclerotherapy than the other authors’ practices. It is also possible that veins treated with CAC may respond differently. It has been our observation that cyanoacrylate can be visualized by postprocedure ultrasound to extend into occluded branches draining into the saphenous vein for a distance of about a 5–10 mm from the truncal vein. This branch closure could theoretically help in branch resolution.

Limitations

There are several limitations to this study. It is a single arm design and relatively small sample size at a single center. Some endpoints may be biased positively or negatively by the absence of a concurrent comparator group, and there may be some patient bias in reporting QOL measures as the patients recognized that branch treatment, if necessary, would be completed at three months. As such, they may have “anticipated” a better result in the future when completing QOL assessments. While this three-month data improve upon the previously reported one-month data, it is still relatively short-term follow-up. One-year data have been collected and publication will be forthcoming.

In conclusion, at three months, CAC is a safe and efficacious procedure for the treatment of venous disease caused by refluxing truncal veins. The extent of adjunctive procedures required at three months was less than predicted by the treating physicians. Treatment of multiple venous segments in a single session was well tolerated by patients. Efficacy as measured by complete vein closure and improvements in QOL was high.

Footnotes

Acknowledgements

The authors would like to acknowledge the work of Dr Daniel Pepper, Dr Leonard Su, and Micah Pepper, MPH, Lake Washington Vascular Surgeons for their assistance in the conduct of this study.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Gibson was the Principal Investigator on the study. She serves on the scientific advisory board for Medtronic, and receives research support from Medtronic. Dr Ferris is a consultant for Medtronic. Dr Minjarez has no conflicting interests. Krissa Gunderson has no conflicting interests.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was an investigator-initiated study funded in part by a research grant from Medtronic, Santa Rosa, CA, USA.

Ethical approval

Ethical approval was obtained from Western Institutional Review Board (WIRB)

Guarantor

KGi

Registration

This study was registered on ClinicalTrials.gov (NCT02585726) prior to first subject enrollment

Contributorship

KGi researched literature and conceived the study. KGi, BF, and RM were involved in protocol development. KGi and KGu gained ethical approval. KGi, RM, BF performed patient recruitment and treatment. KGi performed data analysis. KGi wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

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