Five-year extension study of patients from a randomized clinical trial (VeClose) comparing cyanoacrylate closure versus radiofrequency ablation for the treatment of incompetent great saphenous veins

Five-year extension study of patients from a randomized clinical trial (VeClose) comparing cyanoacrylate closure versus radiofrequency ablation for the treatment of incompetent great saphenous veins Nick Morrison, MD,a Kathleen Gibson, MD,b Michael Vasquez, MD,c Robert Weiss, MD,d and Andrew Jones, MD,e Mesa, Ariz; Bellevue, Wash; Buffalo, NY; Hunt Valley, MD; and Bend, Ore

ABSTRACT Objective: The proprietary cyanoacrylate closure (CAC) system vs radiofrequency ablation (RFA) trial (VenaSeal Sapheon Closure System Pivotal Study [VeClose]) showed that CAC, a nontumescent, nonthermal, nonsclerosant ablation technique, was effective and noninferior to RFA in vein closure with good 36-month outcomes. Conducted under a separate protocol, the aim of this extended follow-up was to assess the long-term safety and effectiveness of CAC and RFA for the treatment of incompetent great saphenous veins (GSV) at 5 years (60 months) of follow-up. Methods: This 60-month extension study was conducted for all patients who completed the randomized VeClose study and who were willing to participate. The pivotal VeClose study included patients with symptomatic moderate to severe varicosities (Clinical, Etiology, Anatomy, and Pathophysiology [CEAP] class C2-C4b) and symptomatic GSV incompetence who were randomly assigned (1:1) to either CAC or RFA. The primary outcome measure of this 60-month extension study was complete closure of the target vein, with planned exploratory analysis of noninferiority. Secondary outcomes included CEAP class; completion of the Venous Clinical Severity Score, EuroQol-Five Dimension survey, and Aberdeen Varicose Vein Questionnaire; patient satisfaction with treatment; adverse events (AEs) related to target GSV; and details of adjunctive procedures. Results: A total of 89 patients completed the 60-month visit, which included 47 from the CAC group, 33 from the RFA group, and 9 CAC roll-in patients. No new recanalization events have been observed in the groups between 36 and 60 months of follow-up. At 60 months, Kaplan-Meier estimates for freedom from recanalization in the randomized CAC and RFA groups were 91.4% and 85.2%, respectively, demonstrating noninferiority of CAC compared with RFA. Both groups demonstrated sustained improvements in EuroQol-Five Dimension and quality of life measures through 60 months. Whereas patients assigned to C0 or C1 clinical class were excluded from the original study, more than half of all returning patients (64% [57/89]) were now assigned to C0 or C1, suggesting an improved clinical class from baseline. Furthermore, 41.1% of returning CAC patients and 39.4% of returning RFA patients are presently at least two CEAP clinical classes lower than at baseline. No long-term device- or procedure-related serious AEs occurred in either group between 36- and 60-month follow-up. Conclusions: CAC and RFA were effective in achieving complete target vein closure of the GSV at long-term follow-up, with CAC demonstrating continued noninferiority to RFA. CAC was also associated with sustained improvements in symptoms and quality of life, lower CEAP class, and high level of patient satisfaction without serious AEs between 36 and 60 months. (J Vasc Surg: Venous and Lym Dis 2020;-:1-12.) Keywords: Cyanoacrylate closure; Radiofrequency ablation; Great saphenous vein insufficiency; Long-term outcomes

From the Center for Vein Restoration, Mesaa; Lake Washington Vascular, Bellevueb; Venous Institute of Buffalo, Buffaloc; Maryland Laser Skin & Vein, Hunt Valleyd; and Inovia Vein Specialty Center, Bend.e This work was funded by Medtronic. Medtronic and the investigators collaborated on study design. Data collection was performed by the investigators.

investigator. R.W. has been paid a consulting fee by Medtronic for data collection as an investigator. Presented at Charing Cross International Symposium, London, United Kingdom, April 15-18, 2019. Correspondence: Nick Morrison, MD, Center for Vein Restoration, 1500 S

Medtronic and the investigators collaborated on analysis and interpretation

Dobson Rd, Ste 310, Mesa, AZ 85202 (e-mail: [email protected]).

of data. Indegene assisted investigators with manuscript writing. Manuscript

The editors and reviewers of this article have no relevant financial relationships to

submission was completed by the corresponding author. ClinicalTrials.gov

disclose per the Journal policy that requires reviewers to decline review of any

identifier: NCT03455699. Author conflict of interest: N.M. has been paid a consulting fee by Medtronic as

manuscript for which they may have a conflict of interest. 2213-333X

a consultant, as a speaker, and for data collection as an investigator. K.G. has

Copyright Ó 2020 The Authors. Published by Elsevier Inc. on behalf of the So-

been paid a consulting fee by Medtronic as a consultant, a member of their

ciety for Vascular Surgery. This is an open access article under the CC BY-NC-

Scientific Advisory Board, and a speaker and for data collection as an investigator. A.J. has been paid a consulting fee by Medtronic as a consultant, as a

ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.jvsv.2019.12.080

speaker, and for data collection as an investigator. M.V. has been paid a consulting fee by Medtronic as a speaker and for data collection as an

1

2

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders ---

Chronic venous disease (CVD) is a common and progressive medical condition affecting >30 million adults in the United States.1 The sequelae of CVD have a significant impact on patients’ quality of life (QoL) and increase the health care burden, with an estimated $1 billion incurred annually for treatment in the United States.2 The management of CVD and saphenous insufficiency has undergone dramatic changes during the past two decades, with minimally invasive endovenous techniques supplanting conventional surgical therapy.3 Endovenous therapies including radiofrequency ablation (RFA; proprietary segmental thermal ablation) and endovenous laser ablation (EVLA) have been demonstrated to be safe and effective in 2- and 5-year follow-up studies.4-6 In 2011, the Society for Vascular Surgery and the American Venous Forum published a guideline suggesting that with a grade 1 recommendation and level of evidence B, thermal ablation using laser or radiofrequency is a safe, effective procedure and should be preferred to conventional surgery because of a shorter recovery time, less pain, and lower morbidity.2 RFA and EVLA are associated with high closure rates, good safety profiles, and early recovery of the patient.4-10 Of note, anatomic closure has previously been shown to correlate with clinical improvement, with a closure rate of 100% being the best possible outcome at 5 years.7 Thermal ablation reduces side effects often associated with truncal, surgical extirpation, such as paresthesia and phlebitis.11-13 However, both RFA and EVLA require the use of tumescent anesthesia (TA); this not only adds time to the procedure, but multiple tumescent injections used during the procedure can cause postprocedural ecchymosis, pain, and hematoma.11,14 Many patients are needle averse, making TA less desirable for them. To circumvent the problems associated with TA, nonthermal, nontumescent therapies for treatment of saphenous insufficiency have been developed. One of these nonthermal, nontumescent therapies is the minimally invasive technique of cyanoacrylate closure (CAC) using the VenaSeal (Medtronic, Minneapolis, Minn) system (beginning in 2011), which involves the endovenous delivery of cyanoacrylate adhesive to the vein, inducing a foreign body response resulting in fibrosis and closure. CAC is a unique nonthermal, nontumescent medical device that unlike a pharmacochemical modality does not require the use of a sclerosant. Sclerosant techniques expose the circulatory system, far remote from the local injection area, to byproducts of endothelial destruction thought to be responsible for adverse side effects. On the other hand, the high viscosity and rapid polymerization of the proprietary cyanoacrylate produce a highly localized effect at the site of administration, and it has not been shown to migrate. Consequently, CAC is referred to as a nonthermal, nontumescent, nonsclerosant technology. The clinical benefits of the CAC technique were demonstrated in a first-in-human feasibility trial15-17 and

2020

ARTICLE HIGHLIGHTS d

d

d

Type of Research: Follow-up study of a prospective, randomized, controlled, multicenter trial Key Findings: At 60-month follow-up of 56 patients treated with cyanoacrylate closure (CAC) and 33 patients with radiofrequency ablation for incompetent great saphenous veins, there were no new recanalizations, with freedom from recanalization in the randomized CAC and radiofrequency ablation groups of 91.4% and 85.2%, respectively. Both techniques resulted in stable and sustained improvement in symptoms and quality of life, with no serious adverse events reported between 36 and 60 months. Take Home Message: At 5 years, treatment with the proprietary CAC system was safe and effective in the long-term treatment of great saphenous vein incompetence.

a single-arm, multicenter, cohort study, the European Sapheon Closure System Observational Prospective (eSCOPE) study.10 The closure rates at 12 months reported in the first-in-human and eSCOPE trials were similar at 92.1%17 and 92.9%,10 respectively. The initial 3-month outcomes of the U.S. VenaSeal Sapheon Closure System Pivotal Study (VeClose) demonstrated noninferiority of CAC compared with RFA and showed excellent great saphenous vein (GSV) closure rates with good safety profiles. Postprocedural ecchymosis was significantly lower in the CAC group compared with the RFA group because CAC does not require TA.18 In the subsequent 12-, 24-, and 36-month follow-ups of the VeClose trial, the closure rates were excellent and similar in both the CAC and RFA groups. Furthermore, CAC successfully demonstrated continued noninferiority to RFA, the standard treatment, along with additional benefits, such as no requirement for TA or compression stockings.3,19-21 Nonetheless, long-term follow-up studies are required to establish the durability of treatment in terms of long-term effectiveness and safety. Hence, the aim of this extended follow-up study was to assess the long-term effectiveness and safety of CAC and RFA 5 years after the intervention in patients with incompetence of the GSV.

METHODS Study design. The original VeClose trial was a prospective, randomized, controlled, multicenter trial to assess the effectiveness of CAC compared with RFA in patients with incompetent GSV. The trial was conducted at 10 participating centers in the United States between March and September 2013. All investigators were independent research sites. Stockholders of the parent company, Sapheon, were not allowed to participate in the study as investigators. An investigational device exemption (IDE) was granted by the U.S. Food and

Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume

-,

Number

Morrison et al

3

-

Drug Administration for this study. All the trial centers obtained approvals from a central Institutional Review Board before enrollment, and written informed consent was obtained from participants after their eligibility was confirmed. A detailed description of the study design, eligibility criteria, and outcomes for previous analyses through 36-month follow-up has been published previously.18 This 60-month follow-up study was conducted in nine centers as an extension study under a separate protocol approved by a central Institutional Review Board; it enrolled patients of the VeClose IDE trial who were able to be contacted, provided written informed consent, and were able to complete the duplex ultrasound examination and other visit requirements at 5 years. The original consent for the IDE study did not include a 60-month visit, so patients had no expectation of being contacted to be reconsented for this new study. Patients. Because this follow-up study evaluated 89 patients from the original IDE study, this section describes how the cohorts were initially established. The initial IDE study enrolled patients aged 21 to 70 years with symptomatic moderate to severe varicosities (Clinical, Etiology, Anatomy, and Pathophysiology [CEAP] class C2-C4b; C0, C1, C5, and C6 patients were excluded) and symptomatic GSV incompetence with a reflux time of $0.5 second assessed in the standing position with duplex ultrasound. Patients who had hemodynamically significant reflux of the small saphenous vein or anterior accessory GSV, previous treatment of venous disease in the target limb, symptomatic peripheral artery disease, history of deep venous thrombosis (DVT) or pulmonary embolism, or aneurysm of the target GSV with >12-mm diameter were excluded from the trial. After eligibility was confirmed for the initial IDE and the extension studies, patients underwent a baseline examination that included a brief and focused physical examination by the investigators for vascular history, completion of Venous Clinical Severity Score (VCSS) assessment and CEAP classification, and duplex ultrasound examination of both legs. Patients also completed the EuroQol-5 Dimension (EQ-5D) QoL survey and the Aberdeen Varicose Vein Questionnaire (AVVQ).22,23 Participants in the IDE study were randomized in a 1:1 fashion to either CAC (VenaSeal system; n ¼ 108) or RFA (ClosureFast system [Medtronic, Minneapolis, Minn]; n ¼ 114). From the original enrollment, randomization was stratified by study site and used random block sizes of four or six; assignments were obtained through automated telephone service connected to a password-protected randomization table. Roll-in cases (nonrandomized; first two cases at each trial center; n ¼ 20) were treated with CAC to ensure familiarity with the device and procedure.18

Devices and procedures. In patients randomized to CAC, the target GSV was treated with the VenaSeal system as described previously.18 Briefly, the target GSV was assessed by ultrasound, and a 7F introducer sheath coupled with a 5F delivery catheter was used to deliver the cyanoacrylate adhesive (0.1-mL aliquots) twice, 1 cm apart, followed by hand compression at the treated segment for 3 minutes. Subsequent 0.1-mL aliquots of cyanoacrylate adhesive were delivered at 3-cm intervals along the target treatment area, and compression with the ultrasound probe and free hand was held for 30 seconds at each treated segment. Once the target vein was treated, the introducer sheath and delivery catheter were removed. Patients assigned to RFA were treated with the ClosureFast system according to the manufacturer’s instructions for use. Patients of both groups used postprocedure compression stockings for 3 continuous days and for another 4 days during waking hours only. Ipsilateral and contralateral adjunctive varicose vein treatments were not allowed until 4 months after completion of the procedure to avoid confounding the study’s primary end point but were allowed thereafter in consultation with the physician, specifically to residual varicosities or the untreated distal GSV segment. Postprocedural follow-up. After the procedure, patients visited the investigational center on day 3 and at months 1, 3, 6, 12, 24, and 36 as part of the IDE study. For the extension study at 60 months, patients who were successfully contacted and were interested in participation provided written informed consent for this extended visit. At every follow-up visit from month 3, including the 60-month visit, the physicians completed VCSS and CEAP assessments, and the patients completed the AVVQ and EQ-5D QoL survey. The EQ-5D consists of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) assessed by a three-level questionnaire (no problems, some or moderate problems, and extreme problems) as well as the visual analog health scale on a vertical score of 0 to 100.24 The health state preferences measured by the EQ-5D questionnaire were then converted to utility scores using the preference weight for the general U.S. population, with values ranging from 0 (worst health condition) to 1 (good health).25 Doppler ultrasound examination was performed on the treated limb by vascular technologists and interpreted by the physician. Patients completed a questionnaire on satisfaction with treatment and whether they would choose the same treatment again. The response choices were very dissatisfied, somewhat dissatisfied, somewhat satisfied, and very satisfied. Last, patients were asked at each visit whether they would agree to have the procedure again if needed.

4

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders ---

At each follow-up visit, investigators at the trial sites were asked to record information on any adverse events (AEs), including the date of onset, relationship of the AEs to the device and procedure, and any actions taken on the AEs. Safety was reviewed by an independent Data and Safety Monitoring Board through 12-month follow-up. AEs reported in the follow-up visits from the index procedure through month 36 were previously published.3,18-20 The site-reported occurrence of serious AEs, pulmonary embolisms, DVT events occurring in either leg, and AEs occurring on the treated limb after the 36-month follow-up visit were required to be reported during the 60-month follow-up visit. Any AE was considered serious if it led to death; serious deterioration of a patient’s health; or fetal distress, fetal death, congenital abnormality, or birth defect. Planned hospitalization for any pre-existing condition was not considered a serious AE. Statistical analysis. Data were analyzed on a modified intention-to-treat basis by retaining allocation to the two intervention groups according to randomization and by including all patients in whom the end point information was available. The primary end points of this study were the frequency of complete closure of the target vein at 60 months and time to recanalization through 60 months. Complete closure was defined as Doppler ultrasound examination (including color flow, compression, and pulsed Doppler) showing closure along the entire treated target vein segment with no discrete segments of patency exceeding 5 cm in length.18 Differences in complete closure between the groups were assessed using Fisher exact test. The freedom from recanalization in both the groups was estimated using Kaplan-Meier method, and noninferiority at significance level of .025 was demonstrated assuming a lower limit of 97.5% bootstrapped confidence interval of 3.5% of the difference between the groups greater than 10%. The secondary end points were changes in VCSS, AVVQ score, and EQ-5D score at 60 months compared with baseline; CEAP class; satisfaction with treatment; AEs related to target GSV; and adjunctive procedures performed on the study limb. Changes in VCSS, AVVQ score, and EQ-5D index and visual analog scale scores from baseline to month 60 were compared within each treatment group by paired t-test. Patient satisfaction with treatment between the groups was calculated using Wilcoxon test. The log-rank test was planned to compare the AEs between groups. Continuous data were expressed as mean 6 standard deviation and categorical data as percentages. Independent t-test was performed for continuous variables, c2 test or Cochran-MantelHaenszel modified ridit score test for categorical variables, and Fisher test for binary variables to test the differences between the two treatment groups. All the

2020

analyses were performed using SAS 9.4 software (SAS Institute, Cary, NC). P values < .05 between the groups were considered statistically significant.

RESULTS Patient follow-up. A total of 89 patients consented and completed the 60-month follow-up visit, 47 in the CAC group, 33 in the RFA group, and 9 in the roll-in group (nonrandomized; first two cases at each trial center were treated with CAC to ensure familiarity with the device and procedure in the original IDE study).18 The patients’ characteristics for this 60-month follow-up visit are given in Table I. The mean length of the treated GSV in the CAC and RFA groups was 32.1 6 11.8 cm and 35.5 6 15.2 cm, respectively (P ¼ .267). The original IDE study included 242 participants, 108 in the CAC group, 114 in the RFA group, and 20 in the roll-in group. In comparing the total VeClose IDE cohort (n ¼ 242) enrolled in 2013 with the group that participated in the 60-month follow-up study (n ¼ 89), there were no differences in age (P ¼ .308), sex (P ¼ .755), initial CEAP clinical class (P ¼ .916), VCSS (P ¼ .445), AVVQ score (P ¼ .957), or EQ-5D score (P ¼ .690). Primary outcomes. No new GSV failures occurred between 36- and 60-month visits in either group. At month 60, complete closure of the GSV was reported in 93.6% of patients (44/47) in the CAC group and 100% of patients for both the RFA group (33/33) and CAC roll-in group (9/9) as assessed by the investigator with duplex ultrasound. As roll-in patients also received CAC treatment, the complete closure rate for the combined roll-in and randomized CAC groups was 94.6% (53/56). There was no significant difference in closure rates between the CAC roll-in, CAC randomized, and RFA groups (P ¼ .292). In the CAC group, three limbs had patent segments of the treated GSV, which was also noted in the 3-month (one limb), 12-month (three limbs), 24month (two limbs), and 36-month (two limbs) duplex ultrasound examinations. No recanalization of an entire treated GSV was observed, and the patients with segmental recanalization remained asymptomatic. Kaplan-Meier freedom from recanalization analysis demonstrated noninferiority of the CAC group compared with the RFA group at a significance level of .025 (noninferiority based on one-sided 97.5% confidence interval with lower limit of 3.5% and margin of 10%) through the 60-month follow-up period (91.4% vs 85.2%, respectively). These rates remained unchanged from the 36-month follow-up visit, indicating that no new GSV failures occurred between 36- and 60-month visits in either group (Fig 1). Secondary outcomes. Venous disease symptoms and QoL measures improved after the index procedure, and this improvement was sustained through 60-month follow-up. The mean VCSSs, which were comparable at baseline, significantly declined (improved) by 75% from

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume

-,

Number

5

-

Table I. Baseline characteristics of patients at 60 months of follow-up of the VeClose trial Characteristics

CAC (n ¼ 47)

RFA (n ¼ 33)

Age, years

51.11 6 11.52

50.37 6 8.98

.757a

5 (15.2)

.769b

Male

9 (19.1)

P value

BMI, kg/m

26.70 6 4.87

26.71 6 5.77

.994a

GSV treatment length, cm

32.09 6 11.83

35.46 6 15.15

.267a

Proximal vein diameter, mm

6.44 6 2.04

5.91 6 1.76

.302a

2

<8 mm

40 (85.1)

$8 mm

7 (14.9)

30 (90.9) 3 (9.1)

CEAP class C2

29 (61.7)

19 (57.6)

C3

13 (27.7)

10 (30.3)

4 (8.5)

4 (12.1)

C4a C4b

1 (2.1)

.711c

0 (0.0)

VCSS

5.17 6 2.43

5.06 6 2.16

.836a

AVVQ score

18.76 6 9.60

18.72 6 7.88

.987a

EQ-5D health thermometer score

86.70 6 14.51

82.42 6 14.41

.197a

AVVQ, Aberdeen Varicose Vein Questionnaire; BMI, body mass index; CAC, cyanoacrylate closure; CEAP, Clinical, Etiology, Anatomy, and Pathophysiology; EQ-5D, EuroQol-5 Dimension health thermometer as assessed by visual analog scale; GSV, great saphenous vein; RFA, radiofrequency ablation; VCSS, Venous Clinical Severity Score. Categorical variables are presented as number (%). Continuous variables are presented as mean 6 standard deviation. a P value comparing CAC and RFA based on independent sample t-test. b P value comparing CAC and RFA based on Fisher exact test. c P value comparing CAC and RFA based on Cochran-Mantel-Haenszel modified ridit score test for difference in mean scores with C4a and C4b considered the same category.

baseline in the CAC group and by 72% in the RFA group (for both, P < .0001; Fig 2). Similarly, AVVQ scores (disease-specific QoL) significantly declined (improved) by 55% and 67% (Fig 3, A; for both, P < .0001). The EQ-5D index scores (Fig 3, B; generic QoL), which were

modestly depressed at baseline (index scores at baseline, mean 6 standard deviation: CAC, 0.86 6 0.10; RFA, 0.84 6 0.07), improved by 15% and 12% in the CAC and RFA groups, respectively, at month 60 at statistically significant levels (at month 60: CAC, 0.97 6 0.08; RFA,

Fig 1. Kaplan-Meier analysis of complete closure rate of the target vein for the cyanoacrylate closure (CAC) and radiofrequency ablation (RFA) treatment groups. The Kaplan-Meier figure represents time to the event.

6

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders ---

2020

Fig 2. Mean Venous Clinical Severity Score (VCSS) at different time periods in the cyanoacrylate closure (CAC) and radiofrequency ablation (RFA) treatment groups during 60 months. SE, Standard error.

0.94 6 0.11; for both, P < .0001). The EQ-5D visual analog scale scores also improved by 22% and 15% (Fig 3, C) from baseline in the CAC and RFA treatment groups (CAC, P ¼ .236; RFA, P ¼ .079), respectively. Of note, after CAC intervention, significant improvement was seen in the pain/discomfort domain with 91.5% (43/47) of the patients reporting no pain at month 60. This is a notable change from baseline, at which only 27.7% (13/47) of patients reported no pain. Mobility and usual activities were the other domains for which almost all patients reported improvement from baseline (Table II). Clinical class C0 and C1 patients were excluded from the VeClose trial. However, more than half of all patients (64% [57/89]) in this study are now assigned to class C0 or C1. Individual analysis of CAC patients (roll-in and randomized) and RFA patients in this study revealed that 41.1% (23/56) and 39.4% (13/33), respectively, resulted in changes of at least two CEAP clinical classes lower than at baseline (Fig 4). More specifically, 66.7% (10/15) of CAC (combined roll-in and randomized) patients initially assigned to CEAP C3 are now C0 or C1, and 16.7% (1/6) of CAC (combined roll-in and randomized) patients initially assigned to C4a or C4b are now C0, C1, or C2 (Fig 4). Furthermore, 50% (5/10) of RFA patients initially assigned to C3 are now C0 or C1, and 75% (3/4) of RFA patients initially assigned to C4a or C4b are now C0, C1, or C2 (Fig 4).

The proportions of patients who expressed being very satisfied or somewhat satisfied with the procedures at the time of treatment were 97.9% (91.5% and 6.4%, respectively) in the CAC group and 97% (90.9% and 6.1%, respectively) in the RFA group. The differences were not statistically significant (P ¼ .921). At the 60-month follow-up, there was no statistically significant difference between the groups in the number of patients who were very satisfied or somewhat satisfied with the treatments (P ¼ .340; Table III). No target limb AEs, serious AEs, pulmonary embolisms, or DVT events were reported between months 36 and 60. Specifically, no delayed hypersensitivity reactions were identified in patients of CAC or RFA groups between 36 and 60 months. Adjunctive treatments, sclerotherapy or phlebectomy or other procedures, were allowed in the follow-up visits after month 3, primarily to eliminate incompetent tributaries, residual varicosities, and incompetent untreated distal GSVs. Between the 36- and 60-month follow-up visit, two (4.3%) and three patients (9.1%) in the CAC and RFA treatment groups, respectively, received sclerotherapy (P ¼ .644), but none in either group received phlebectomy (data not shown in table). The interpretation of overall level of satisfaction with the treatment was high, with 89.4% in the CAC group

Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume

-,

Number

Morrison et al

7

-

Fig 3. Aberdeen Varicose Vein Questionnaire (AVVQ) score (A) and EuroQol-5 Dimension (EQ-5D) index score (B) and EQ-5D health thermometer as assessed by visual analog scale (C) at different time periods in the cyanoacrylate closure (CAC) and radiofrequency ablation (RFA) treatment groups during 60 months. SE, Standard error.

and 93.9% in the RFA group responding that they would definitely have the procedure again at the time of the initial treatment (Table IV). At 60-month follow-up, a slightly higher (but not statistically significant) proportion of patients in the CAC group responded that they would definitely have the treatment again compared with the RFA group (93.6% vs 87.9%; P ¼ .374).

DISCUSSION Previous reports from the VeClose trial demonstrated positive results with the use of CAC compared with RFA through 36 months of treatment in patients with incompetent GSVs.3,18-21 The long-term follow-up data

presented in this extension study are important to assess the continued durability of the treatment. The observations at month 60 are an extension of the 36-month follow-up visit to gain additional insights for comparison of CAC with RFA without significant further intervention and also to assess long-term performance of CAC. At each time period previously studied, the anatomic success of CAC was comparable to RFA.19 The results of this 5-year long-term follow-up study are consistent with the previous VeClose trial at 3, 12, 24, and 36 months, with similar closure rates, thus establishing durability of CAC and RFA treatment.19 In addition to maintaining consistent closure rates through 60 months, CAC also

8

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders ---

2020

Table II. Comparison of EuroQol-5 Dimension (EQ-5D) descriptive system questionnaires at baseline and at 60 months in the cyanoacrylate closure (CAC) and radiofrequency ablation (RFA) groups Visit

CAC (n ¼ 47)

RFA (n ¼ 33)

P valuea

Baseline Mobility

.5504

I have no problems in walking about

89.4 (42/47)

84.8 (28/33)

I have some problems in walking about

10.6 (5/47)

15.2 (5/33)

I am confined to bed

0.0 (0/47)

0.0 (0/33)

Self-care I have no problems with self-care

1.0000 100.0 (47/47)

100.0 (33/33)

I have some problems washing or dressing myself

0.0 (0/47)

0.0 (0/33)

I am unable to wash or dress myself

0.0 (0/47)

0.0 (0/33)

I have no problems with performing my usual activities

85.1 (40/47)

78.8 (26/33)

I am unable to perform my usual activities

14.9 (7/47)

21.2 (7/33)

I am unable to perform my usual activities

0.0 (0/47)

0.0 (0/33)

I have no pain or discomfort

27.7 (13/47)

21.2 (7/33)

I have moderate pain or discomfort

70.2 (33/47)

78.8 (26/33)

2.1 (1/47)

0.0 (0/33)

93.6 (44/47)

84.8 (28/33)

I am moderately anxious or depressed

6.4 (3/47)

15.2 (5/33)

I am extremely anxious or depressed

0.0 (0/47)

0.0 (0/33)

100.0 (47/47) 0.0625b

93.9 (31/33) 0.2500b

Usual activities

.4669

Pain

I am extremely anxious or depressed

.6359

Anxiety/depression I am not anxious or depressed

.2009

Month 60 Mobility I have no problems in walking about

.0894

I have some problems in walking about

0.0 (0/47)

6.1 (2/33)

Mobility: I am confined to bed at 60 months

0.0 (0/47)

0.0 (0/33)

Self-care I have no problems with self-care

1.0000 100.0 (47/47) NAb

100.0 (33/33) NAb

I have some problems washing or dressing myself

0.0 (0/47)

0.0 (0/33)

I am unable to wash or dress myself

0.0 (0/47)

0.0 (0/33)

Usual activities I have no problems with performing my usual activities I am unable to perform my usual activities I am unable to perform my usual activities

.3650 97.9 (46/47) 0.0313b 2.1 (1/47) 0.0% (0/47)

93.9 (31/33) 0.1250b 6.1 (2/33) 0.0% (0/33)

Pain

.2007 91.5 (43/47) <.0001b

81.8 (27/33) <.0001b

Pain: I have moderate pain or discomfort at 60 months

8.5 (4/47)

18.2 (6/33)

I am extremely anxious or depressed

0.0 (0/47)

0.0 (0/33)

95.7 (45/47) 1.0000b

84.8 (28/33) 1.0000b

I am moderately anxious or depressed

2.1 (1/47)

12.1 (4/33)

I am extremely anxious or depressed

2.1 (1/47)

3.0 (1/33)

I have no pain or discomfort

Anxiety/depression I am not anxious or depressed

.0977

N/A, Not applicable. Values are reported as percentage (n/N). a P value comparing VenaSeal Closure System and RFA based on Cochran-Mantel-Haenszel modified ridit test for difference in row mean scores. b P value comparing 60 months with baseline based on Wilcoxon signed rank test.

Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume

-,

Number

Morrison et al

9

-

Fig 4. Change in C2 to C4b of the Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification from baseline to month 60 in the cyanoacrylate closure (CAC; roll-in and randomized) and radiofrequency ablation (RFA) treatment groups.

showed a high rate of freedom from recanalization with no new failures reported, thereby further confirming the durability of the treatment and noninferiority to RFA. In this study, 5-year closure rate for CAC was similar to that observed for RFA,10 EVLA,8 and surgery26 in long-term, prospective studies. However, the long-term GSV closure rate with CAC was 20% to 40% higher than that of foam sclerotherapy.8,26,27 Recanalization or restoration of the lumen of a vein after it has been occluded is well described in endovenous treatment. In this study, the Kaplan-Meier estimates for freedom of recanalization in the CAC group was found to be 91.4%, which was higher than those reported for foam sclerotherapy (68.4%),8 EVLA (82.1%), and stripping (89.9%)7 and in the same range as that reported for RFA (93.2%)8 at 5 years. The long-term clinical impact of recanalized segments of the GSV is unknown. However, in an earlier study, recanalization after EVLA and stripping did not influence VCSS or QoL.7 The factors contributing to recanalization after CAC treatment need to be investigated, but studies have shown that increasing vein diameter (>6 mm) is an independent risk factor for recanalization of GSV after EVLA and foam sclerotherapy at 12 months.28 Type of device and length of treated vein were other predictors for recanalization after EVLA.27 The results of the secondary outcomes concerning VCSS, disease-specific AVVQ score, and EQ-5D QoL score

at 5 years after CAC and RFA were comparable with significant improvement from baseline to month 6 that persisted through 60 months.3 A similar trend in VCSS was seen in a previous 5-year follow-up study of RFA wherein the VCSS significantly improved with maintenance of low scores throughout the 5-year follow-up.10 The patient-reported health status, which includes AVVQ and EQ-5D scores reflecting both disease-specific and general QoL-related health status, also showed stable improvement from baseline to 60 months in both CAC and RFA groups. The results of the QoL measures were similar to earlier observations comparing other techniques like EVLA, surgery, RFA, and foam sclerotherapy at 5 years.7,29,30 Although CEAP classification is a descriptive instrument and not designed to measure outcomes over time, analysis of returning patients in Fig 4 assigned to C2 to C4b clinical class at baseline demonstrates at least two clinical classes lower at 60 months in 41.1% of CAC patients (roll-in and randomized) and 39.4% of RFA patients, suggesting clinical improvement (Fig 4). Lowering by one clinical class was seen in 18 of 56 (32.1%) CAC (roll-in and randomized) patients and in 11 of 33 (33.3%) RFA patients (Fig 4). No change was noted in 13 of 56 (23.2%) CAC (roll-in and randomized) patients and in 7 of 33 (21.2%) RFA patients (Fig 4). Finally, a higher CEAP class compared with baseline was identified in two (3.6%)

Morrison et al

10

Journal of Vascular Surgery: Venous and Lymphatic Disorders ---

Table III. Treatment satisfaction in the cyanoacrylate closure (CAC) and radiofrequency ablation (RFA) groups at the time of treatment and 60 months P valuea

Table IV. Decision to have treatment again in the cyanoacrylate closure (CAC) and radiofrequency ablation (RFA) groups at the time of treatment and 60 months CAC (n ¼ 47)

RFA (n ¼ 33)

P valuea

Not have again

2.1 (1/47)

0.0 (0/33)

.466

Might have again

8.5 (4/47)

6.1 (2/33)

89.4 (42/47)

93.9 (31/33)

Not have again

0.0 (0/47)

0.0 (0/33)

Might have again

6.4 (3/47)

12.1 (4/33)

93.6 (44/47)

87.9 (29/33)

CAC (n ¼ 47)

RFA (n ¼ 33)

0.0 (0/47)

0.0 (0/33)

Somewhat dissatisfied

2.1 (1/47)

3.0 (1/33)

Somewhat satisfied

6.4 (3/47)

6.1 (2/33)

Definitely have again

91.5 (43/47)

90.9 (30/33)

Very dissatisfied

0.0 (0/47)

0.0 (0/33)

Somewhat dissatisfied

0.0 (0/47)

3.0 (1/33)

Somewhat satisfied

8.5 (4/47)

12.1 (4/33)

91.5 (43/47)

84.8 (28/33)

Visit Procedure Very dissatisfied

Very satisfied

Visit Procedure

.921

Month 60

Month 60

Very satisfied

2020

.340

Definitely have again

.374

Values are reported as percentage (n/N). a P value comparing CAC and RFA based on Wilcoxon test in the complete case modified intention-to-treat population.

Values are reported as percentage (n/N). a P value comparing CAC and RFA based on Wilcoxon test in the complete case modified intention-to-treat population.

CAC (roll-in and randomized) patients and two (6.1%) RFA patients, suggesting worsening of the patients’ clinical condition (Fig 4). The recurrence of varicose veins after treatment may require multiple, additional interventional modalities within the same treatment session (eg, endovenous thermal ablation plus phlebectomy) or in multiple sessions (eg, laser ablation followed by sclerotherapy to treat tributary veins).2 Our findings demonstrate that both CAC and RFA cohorts were associated with low additional interventional treatment rates at all the evaluation time points beyond 12 months and including the 60-month follow-up. The majority (>60%) of the adjunctive treatments (sclerotherapy and phlebectomy) predictably occurred before year 1,3 which decreased from 12 months, and the rates remained stable through 36 months.19 Only sclerotherapy was administered in the 36- to 60-month period in both CAC and RFA groups. With regard to safety, no target limb AEs, pulmonary embolisms, or DVT events were reported in either the CAC or RFA populations between months 36 and 60, demonstrating the long-term safety of CAC treatment. Reports of abnormal granulomatous reactions after cyanoacrylate ablation have recently appeared in the literature.31 In this study, abnormal granulomatous reactions would have been reported as AEs, and none were seen during the 60-month period. It has been the experience of the primary author that all patients in his cohort within the VeClose trial and this study had cyanoacrylate still visible by ultrasound at 60 months, suggesting a permanent implant. It was not within the scope of these trials to evaluate these implants histologically, so no comment can be made from these studies regarding any normal granulomatous foreign body reaction. Patient satisfaction, admittedly being a somewhat inexact metric, is nonetheless an important indicator

for outcomes of any technology to measure its success. In this study, the favorable clinical outcomes associated with CAC and RFA correlate with a high satisfaction level; 100% and 96.9% of the patients in the CAC and RFA groups, respectively, reported being satisfied with their treatment. Strengths of the combined IDE study and extended 60-month follow-up include its randomized and multicenter design that combines the cumulative experience of various physicians, thus removing the bias of a single center. In addition, the clinical outcomes, symptom scores, and ultrasound assessments were meticulously assessed at scheduled time points. All data were reviewed by external monitors and source verified. The correlation between the investigator and the core laboratory was in complete agreement at 3 months, suggesting that investigator readings used for other time points were sufficiently accurate. The study also has some limitations. One limitation of the original IDE study is that blinding of physicians, patients, and outcome assessors was not possible owing to the nature of the interventions because RFA requires TA and CAC has characteristic findings on ultrasound. The extension study was carried out under a separate protocol and included only patients from the IDE study who were able to be contacted and agreed to participate. The original consent for the IDE study did not include this 60-month visit, so the patients had no expectation of longer follow-up and may have had less motivation to participate (particularly if they were doing well). In addition, there was a 2-year gap between the 3-year and 5-year follow-up, making it that much more difficult to locate patients. Furthermore, it is widely recognized that recruiting patients for a follow-up visit, especially at 5 years, is challenging. There may be various reasons for patients not attending follow-up data collectiondpatients’ lack of interest, patients’ expectations for the outcome of interest were met, or patients’

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders Volume

-,

Number

11

-

having satisfactory outcomes and hence losing interest in the trial. Follow-up may also be lost if participants changed their names, addresses, and phone numbers or because of some unforeseen personal circumstances that may prevent them from completing the trial. Previous research has demonstrated that losses to follow-up are higher when no treatment is needed after surgery, especially with a longer follow-up period when no specific treatment is required.32,33 In patients lost to follow-up, identifying the next of kin or other important contacts is a challenge.34 Despite the challenges that contributed to a smaller sample size, noninferiority of CAC compared with RFA was still demonstrated (noninferiority established by one-sided 97.5% confidence interval with lower limit of 3.5%). The patient satisfaction reported in our study is subjective. Even though there are many standardized and validated patient satisfaction instruments to assess specific aspects of care, these do not apply for the entire spectrum of care as they have limited potential of validity and reliability.35 As a result, the method of measure of patient satisfaction in our study has not been validated.

CONCLUSIONS This is the first 5-year follow-up demonstrating long-term effectiveness of the proprietary CAC system with durable closure and recanalization-free survival rates in patients with saphenous incompetence. Furthermore, CAC is associated with sustained improvements in symptoms, QoL measures, and CEAP class without AE occurrence. The proprietary CAC system outcomes are comparable to RFA treatment, with a high degree of patient satisfaction after 5 years of follow-up. The authors would like to thank Mitchel Goldman of GBK Cosmetic Laser Dermatology, James McEown of Comprehensive Investigational Care Centers, Gabor Matos of Prairie Education & Research Cooperative, Scott McEnroe of Sentara Vascular Specialists, Peter Stratil of Radiology Imaging Associates, and particularly the investigative study centers’ coordinators at each site for the difficult task of bringing patients back for this extension follow-up visit. In addition, the authors thank Yun Peng, MS, for validation of statistical analysis; Monte Madsen, RVT, RPhs, and Sue Kim, DPM, for technical review; Mark Meissner, MD, for analytical assistance; and Ramu Periyasamy, PhD, of Indegene Pvt Ltd, Bangalore, for medical writing support, which was funded by Medtronic Inc (Minneapolis, Minn).

AUTHOR CONTRIBUTIONS Conception and design: NM Analysis and interpretation: NM, KG Data collection: NM, KG, MV, RW, AJ Writing the article: NM

Critical revision of the article: NM, KG, MV, RW, AJ Final approval of the article: NM, KG, MV, RW, AJ Statistical analysis: NM Obtained funding: Not applicable Overall responsibility: NM

REFERENCES 1. McArdle M, Hernandez-Vila EA. Management of chronic venous disease. Tex Heart Inst J 2017;44:347-9. 2. Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Gloviczki ML, et al. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2011;53:2S-48S. 3. Morrison N, Gibson K, Vasquez M, Weiss R, Cher D, Madsen M, et al. VeClose trial 12-month outcomes of cyanoacrylate closure versus radiofrequency ablation for incompetent great saphenous veins. J Vasc Surg Venous Lymphat Disord 2017;5:321-30. 4. Proebstle TM, Alm J, Göckeritz O, Wenzel C, Noppeney T, Lebard C, et al. Three-year European follow-up of endovenous radiofrequency-powered segmental thermal ablation of the great saphenous vein with or without treatment of calf varicosities. J Vasc Surg 2011;54:146-52. 5. Samuel N, Wallace T, Carradice D, Mazari FA, Chetter IC. Comparison of 12-w versus 14-w endovenous laser ablation in the treatment of great saphenous varicose veins: 5-year outcomes from a randomized controlled trial. Vasc Endovascular Surg 2013;47:346-52. 6. Gauw SA, Lawson JA, van Vlijmen-van Keulen CJ, Pronk P, Gaastra MT, Mooij MC. Five-year follow-up of a randomized, controlled trial comparing saphenofemoral ligation and stripping of the great saphenous vein with endovenous laser ablation (980 nm) using local tumescent anesthesia. J Vasc Surg 2016;63:420-8. 7. Rasmussen L, Lawaetz M, Bjoern L, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years. J Vasc Surg 2013;58:421-6. 8. Lawaetz M, Serup J, Lawaetz B, Bjoern L, Blemings A, Eklof B, et al. Comparison of endovenous ablation techniques, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Extended 5-year follow-up of a RCT. Int Angiol 2017;36:281-8. 9. Almeida JI, Kaufman J, Göckeritz O, Chopra P, Evans MT, Hoheim DF, et al. Radiofrequency endovenous ClosureFAST versus laser ablation for the treatment of great saphenous reflux: a multicenter, single-blinded, randomized study (RECOVERY study). J Vasc Interv Radiol 2009;20: 752-9. 10. Proebstle TM, Alm J, Dimitri S, Rasmussen L, Whiteley M, Lawson J, et al. The European multicenter cohort study on cyanoacrylate embolization of refluxing great saphenous veins. J Vasc Surg Venous Lymphat Disord 2015;3:2-7. 11. Anwar MA, Lane TR, Davies AH, Franklin IJ. Complications of radiofrequency ablation of varicose veins. Phlebology 2012;27(Suppl):34-9. 12. Nejm CS, Timi JR, de Araújo WB, Caron FC. Endovenous laser ablation of the great saphenous veindvarying energy may not affect outcome. Phlebology 2017;32:13-8. 13. Tafur AJ, Rathbun S. Varicose veins. In: Creager MA, Beckman JA, Loscalzo J, editors. Vascular medicine: a companion to Braunwald’s heart disease. 2nd ed. Philadelphia: Elsevier Saunders; 2013. p. 639-51.

12

Morrison et al

Journal of Vascular Surgery: Venous and Lymphatic Disorders ---

14. Dexter D, Kabnick L, Berland T, Jacobowitz G, Lamparello P, Maldonado T, et al. Complications of endovenous lasers. Phlebology 2012;27(Suppl):40-5. 15. Almeida JI, Javier JJ, Mackay EG, Bautista C, Cher DJ, Proebstle TM. Thirty-sixth-month follow-up of first-in-human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. J Vasc Surg Venous Lymphat Disord 2017;5:658-66. 16. Almeida JI, Javier JJ, Mackay EG, Bautista C, Cher DJ, Proebstle TM. Two-year follow-up of first human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. Phlebology 2015;30:397-404. 17. Almeida JI, Javier JJ, Mackay E, Bautista C, Proebstle TM. First human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. J Vasc Surg Venous Lymphat Disord 2013;1:174-80. 18. Morrison N, Gibson K, McEnroe S, Goldman M, King T, Weiss R, et al. Randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins (VeClose). J Vasc Surg 2015;61: 985-94. 19. Morrison N, Kolluri R, Vasquez M, Madsen M, Jones A, Gibson K. Comparison of cyanoacrylate closure and radiofrequency ablation for the treatment of incompetent great saphenous veins: 36-month outcomes of the VeClose randomized controlled trial. Phlebology 2019;24: 380-90. 20. Gibson K, Morrison N, Kolluri R, Vasquez M, Weiss R, Cher D, et al. Twenty-four month results from a randomized trial of cyanoacrylate closure versus radiofrequency ablation for the treatment of incompetent great saphenous veins. J Vasc Surg Venous Lymphat Disord 2018;6:606-13. 21. Kolluri R, Gibson K, Cher D, Madsen M, Weiss R, Morrison N. Roll-in phase analysis of clinical study of cyanoacrylate closure for incompetent great saphenous veins. J Vasc Surg Venous Lymphat Disord 2016;4:407-15. 22. Garratt AM, Macdonald LM, Ruta DA, Russell IT, Buckingham JK, Krukowski ZH. Towards measurement of outcome for patients with varicose veins. Qual Health Care 1993;2:5-10. 23. EuroQol Group. EuroQolda new facility for the measurement of health-related quality of life. Health Policy 1990;16: 199-208. 24. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001;33:337-43.

2020

25. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing of the D1 valuation model. Med Care 2005;43:203-20. 26. Vähäaho S, Halmesmäki K, Albäck A, Saarinen E, Venermo M. Five-year follow-up of a randomized clinical trial comparing open surgery, foam sclerotherapy and endovenous laser ablation for great saphenous varicose veins. Br J Surg 2018;105:686-91. 27. van der Velden SK, Biemans AA, De Maeseneer MG, Kockaert MA, Cuypers PW, Hollestein LM, et al. Five-year results of a randomized clinical trial of conventional surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy in patients with great saphenous varicose veins. Br J Surg 2015;102:1184-94. 28. Toniolo J, Chiang N, Munteanu D, Russell A, Hao H, Chuen J. Vein diameter is a predictive factor for recanalization in treatment with ultrasound-guided foam sclerotherapy. J Vasc Surg Venous Lymphat Disord 2018;6:707-16. 29. Wallace T, El-Sheikha J, Nandhra S, Leung C, Mohamed A, Hardwood A, et al. Long-term outcomes of endovenous laser ablation and conventional surgery for great saphenous varicose veins. Br J Surg 2018;105:1759-67. 30. Hamann SS, Giang J, De Maeseneer MR, Nijsten TC, van den Bos RR. Editor’s choicedfive year results of great saphenous vein treatment: a meta-analysis. Eur J Vasc Endovasc Surg 2017;54:760-70. 31. Parsi K, Kang M, Yang A, Kossard K. Granuloma formation following cyanoacrylate glue injection in peripheral veins and arteriovenous malformation. Phlebology 2020;35:115-23. 32. Farrokhyar F, Karanicolas PJ, Thoma A, Simunovic M, Bhandari M, Devereaux PJ, et al. Randomized controlled trials of surgical interventions. Ann Surg 2010;251:409-16. 33. Michaels JA, Brazier JE, Campbell WB, MacIntyre JB, Palfreyman SJ, Ratcliffe J. Randomized clinical trial comparing surgery with conservative treatment for uncomplicated varicose veins. Br J Surg 2006;93:175-81. 34. Ganz PA, Land SR, Antonio C, Zheng P, Yothers G, Petersen L, et al. Cancer survivorship research: the challenge of recruiting adult long term cancer survivors from a cooperative clinical trials group. J Cancer Surviv 2009;3:137-47. 35. Kilbourne WE, Duffy JA, Duffy M, Giarchi G. The applicability of SERVQUAL in cross-national measurements of healthcare quality. J Serv Mark 2004;18:524-33. Submitted Jul 10, 2019; accepted Dec 16, 2019.