SAVVE US pivotal study of patients with severe chronic insufficiency due to deep valvular venous reflux: One-year results after VenoValve implantation

Abstract

Objective

Failure of deep venous valves and associated reflux leads to the progression of chronic venous insufficiency (CVI), culminating in painful, clinically challenging, and costly leg ulcers. Traditional CVI treatments have primarily focused on symptom management, or interventions for superficial veins. This study aimed to show that bioprosthetic valve implantation yields clinically meaningful health improvements and offers a safe and effective treatment for deep venous CVI by addressing the root cause of the condition.

Methods

SAVVE (Surgical Antireflux Venous Valve Endoprosthesis) was a prospective, single-arm, multicenter study to evaluate the performance of a bioprosthetic venous valve device (VenoValve; enVVeno Medical), for femoral vein implantation in patients with venous disease (Clinical-Etiology-Anatomy-Pathophysiology clinical classifications C4b, C4c, C5, and C6) unresponsive to standard of care therapy. Outcome measures included duplex-derived reflux time, the Revised Venous Clinical Severity Score (rVCSS), pain, disease-specific (VEINES-QoL/Sym) and general health-related quality of life (EuroQol 5 Dimensions) measures, technical success of device implantation, ulcer healing (C6 patients), and ulcer recurrence (in C5 and C6 patients). Clinically meaningful improvement was defined as a decrease in rVCSS of at least 3 points.

Results

Between October 2021 and September 2023, 75 patients were enrolled (median age, 65 years; interquartile range, 57-70 years) at 23 institutions. Of the enrolled patients, 61 (81.3%) were men and 16 (21.3%) were Black, Hispanic, or Latino. The device was implanted in 73 patients (97.3%). At 6 months, 23 of 67 implanted patients (34.3%) had a 30% or greater improvement in duplex-derived reflux time. Average rVCSS score improvements were clinically meaningful and statistically significant at 3, 6, and 12 months. At 12 months, 84.6% of implanted patients achieved clinically meaningful improvement, with an average improvement of 7.9 points in rVCSS. Statistically significant improvements in pain and health-related quality of life were reported through 12 months of follow-up. Among patients with C6 disease, healing was observed for 91.6% of ulcers that had a duration of less than 12 months. No unanticipated device-related adverse events were reported. The perioperative major adverse events rate was 30.7% with no mortality. Most patients with major adverse events achieved clinically meaningful improvement in symptoms.

Conclusions

Implantation of the bioprosthetic venous valve yielded important clinical and health-related quality of life benefits in patients with severe CVI.

Article Highlights.

• •Type of Research: Prospective mutlicenter single arm clinical trial for a breakthrough investigational device
• •Key Findings: We enrolled 75 patients with advanced C4b to C6 venous disease and deep valvular reflux. Implantation of the VenoValve resulted in clinically meaningful improvement (Revised Venous Clinical Severity Score change of ≥3) in 84.6% of patients at 12 months. Most C6 patients had ulceration for more than 1 year’s duration (75%) and 84% had ulcer improvement or healing at 12 months after surgery.
• •Take Home Message: The VenoValve surgery provided significant benefits for patients with advanced venous disease and deep valvular reflux who otherwise had no other surgical options.

Chronic venous disorders, which range in severity from spider telangiectasias and reticular veins to recalcitrant venous ulcers, affect up to 70% of the adult population in the United States, with more than 25 million people experiencing symptoms severe enough to warrant a diagnosis of chronic venous insufficiency (CVI).¹ The condition affects up to 17% of men and 40% of women.^2,3 The cost of CVI and venous ulcers represents 1% to 2% of total health care budgets in Western European countries and the United States.⁴ A recent Centers for Medicare and Medicaid Services database analysis estimated that in 2019, approximately 1.5 million Medicare beneficiaries were treated for a venous ulcer or an associated infection.⁵ Across US payers, estimated treatment costs for venous ulcers have been as high as $14 billion annually.6, 7, 8 It is estimated that 1% to 3% of the US population develop venous ulcers, and approximately 50% of patients who develop a venous ulcer are expected to experience recurrent disease despite current standard-of-care treatments.⁹ Venous ulcers can be painfully debilitating and difficult to treat, especially in the presence of deep venous reflux.^9,10

Despite advances in the treatment of superficial venous reflux and deep venous obstruction, there is no curative pharmacological treatment or therapeutic device currently available to correct deep venous valve dysfunction. Standard therapies focus on symptom management with compression and wound care as needed.¹¹ Such strategies are helpful for patients with milder forms of disease but not effective for patients with more advanced Clinical-Etiology-Anatomy-Pathophysiology (CEAP) class C4 to C6 disease.¹² Deep venous valvular surgical reconstruction has been described but is limited to a handful of centers worldwide with no dissemination owing to the variability in techniques and outcomes.¹³ Thus, a widely available surgical option is needed for patients with refractory disease, particularly those with nonhealing venous ulcers or significant debilitation. Such an option has remained elusive and has been referred to as one of the final frontiers of venous disease and the holy grail of venous therapy.14, 15, 16

The VenoValve device (enVVeno Medical Corporation) is a novel bioprosthetic venous valve replacement intended for treatment of deep venous reflux in patients with severe CVI. The device is surgically implanted in the femoral vein and received Breakthrough Device designation from the US Food and Drug Administration. A pilot study in 11 patients with C5 or C6 disease showed promising results with clinically meaningful improvement of 8 points on the Revised Venous Clinical Severity Score (rVCSS) after 1 year of follow-up.¹⁷ This study reports the 1-year results of the Surgical Antireflux Venous Valve Endoprosthesis (SAVVE) pivotal multicenter trial conducted in the United States (Appendix 1, online only).

Methods

Study design

The SAVVE pivotal trial was a prospective, single-arm multicenter study evaluating the performance of a bioprosthetic venous valve device (VenoValve) for femoral vein implantation in patients with severe deep venous CVI (CEAP clinical classification of C4b, C4c, C5, or C6) unresponsive to standard care therapies. An investigational device exemption was approved by the US Food and Drug Administration. The study was approved by the institutional review boards of the respective sites as well as from a central institutional review board (Advarra), and all participating patients provided written informed consent. The trial was registered on clinicaltrials.gov with national clinical trial number NCT04943172.

An independent medical monitor, Clinical Events Committee and Data Monitoring Committee provided trial oversight. An independent core laboratory reviewed all duplex ultrasound imaging studies, assessing implant patency, duplex-derived reflux times, and presence of deep vein thrombosis (DVT) in the treated leg. The core lab also provided review of radiographs of the device to determine its structural integrity. Biostatistical analysis was conducted by the NAMSA statistical team using SAS software (Appendix 2, online only). The first author had access to the data. The first author wrote the manuscript and all co-authors provided input.

Patient eligibility

Adult ambulatory patients (age ≥18 years) diagnosed with deep venous CVI with advanced clinical manifestations CEAP classes C4b to C6 were recruited and screened for eligibility. All patients had deep valvular incompetence, demonstrated on duplex ultrasound examination, with axial deep reflux times of greater than 1000 ms at the level of the popliteal vein. Patients were unresponsive to at least 3 months of standard of care treatment consisting of compression therapy, as well as wound care for patients with venous ulcers. Patients with superficial venous reflux in the saphenous vein or other superficial veins underwent ablation therapies, with almost all of such treatments occurring at least 3 months before the SAVVE procedure. All patients underwent venography to assess the patency of the ipsilateral deep venous system and rule out iliocaval venous outflow obstruction. Patients with significant iliac vein stenosis underwent stenting, with such treatments occurring at least 2 months before device implantation. Patients with bilateral disease had only the most symptomatic limb treated in the study. Patients with an ipsilateral femoral or popliteal venous stent, a hypercoagulable condition, or significant peripheral arterial disease (ankle-brachial index of <0.70) were excluded. Patients with acute venous thromboembolism, sepsis, and contraindication or concern for compliance with anticoagulation were also excluded (Appendix 3, online only).

VenoValve device

The VenoValve consists of a stainless-steel frame housing a preserved, noncoronary leaflet of a porcine aortic valve, with a section of aorta and a porcine mitral valve anterior leaflet stitched together as the supporting wall (Fig 1). Preservation is achieved using glutaraldehyde crosslinking. The device is 21 mm in length and two diameters are available to match the patient's femoral vein diameter: 9 mm and 10 mm. The functional component of the VenoValve is a porcine noncoronary leaflet preserved to maintain natural characteristics similar to a native venous valve leaflet as well as preserving the sinus of Valsalva. The device is designed such that the monocusp leaflet opens and closes under changes in venous pressure and flow rates within the deep venous system owing to the calf pump or deep breathing, thereby functioning as a replacement valve for patients with deep venous CVI owing to valvular incompetence. By reducing the regurgitative volume of blood into the lower extremity deep venous system, it is intended to provide hemodynamic improvement and reduce symptoms such as pain, edema, and venous ulcers, all of which greatly impact quality of life for these patients.

Fig 1.

The VenoValve consists of a noncoronary leaflet of a porcine aortic valve stitched to a stainless steel frame. The arrow points toward the feet for orientation during implantation.

VenoValve surgical technique: The SAVVE procedure

The SAVVE procedure involved surgical implantation of one VenoValve in the femoral vein in the upper mid-thigh region. All implanting physicians received didactic and hands-on training. After administration of general anesthesia and standard prophylactic antibiotics, a 6- to 8-cm incision was made in mid-thigh following on-table ultrasound imaging and localization of the femoral vein. The femoral artery was mobilized, vascular control of the femoral vein was obtained (6 cm), and venous branches were ligated at the site of implantation to allow for full mobilization of the vein. After heparin anticoagulation, a 1.5-cm longitudinal venotomy was performed in the femoral vein to introduce the VenoValve, with the valve leaflet facing the native vein wall and the apex of the V on the valve pointing towards the foot. The venotomy was closed primarily with a running 6-0 Prolene suture. A bovine pericardial patch was used for closure of smaller veins. Four evenly spaced tacking sutures were then placed only in the inflow ring of the VenoValve to prevent migration of the device.¹⁸ After using a duplex scanner (or continuous wave Doppler ultrasound examination) to confirm intraoperative patency and reduction in reflux in the caudal femoral vein, the surgical cavity was meticulously closed in multiple layers to reduce any dead space. Sequential intermittent pumps were applied to both legs after the procedure. Enoxaparin was initiated in the immediate postoperative period at 1 mg/kg subcutaneously every 12 hours. Most patients were discharged home after a one-night hospital stay.

Anticoagulation and monitoring

Enoxaparin was continued for 4 weeks after surgery. The patients were followed clinically and with ultrasound examination at 7 days and 1, 3, 6, and 12 months after surgery and are continuing with yearly appointments up to 5 years. After receiving enoxaparin for 1 month, patients were switched to a direct oral anticoagulant for at least 1 year after surgery. Patient compliance with anticoagulation was assessed using a patient-reported outcome (ePRO) application. The application sent an alert to the site coordinator, the monitor, and the sponsor when noncompliance was detected; the site coordinator was then informed and advised the patient. Use of a direct oral anticoagulant was evaluated in each patient at 1 year and continuation was typically recommended, especially for post-thrombotic patients.

VenoValve effectiveness

Effectiveness outcomes included changes in popliteal duplex-derived reflux time, which was defined as a binary end point with success defined as a 30% or greater improvement at the 6-month follow-up visit, compared with the preoperative baseline. Patency of the device was assessed by color flow on duplex ultrasound evaluation, and functionality was assessed by spontaneity and respirophasicity caudal to the device, also by duplex ultrasound evaluation. Patency of the target vein was evaluated at 7 and 30 days, and at 3, 6, and 12 months, via duplex ultrasound imaging. The incidence of technical success of device implantation (absence of occlusion or other device-related serious adverse event) was evaluated at 30 days. End points also included clinical changes as measured by Revised Venous Clinical Severity Scoring (rVCSS), including the incidence of clinically meaningful improvement (defined as a ≥3-point change) and average rVCSS improvement, both assessed at 3, 6, and 12 months in comparison with baseline.^19,20 Quality of life was assessed by patient report of pain (rated using a visual analog scale [VAS]), VEINES-QoL/Sym, and EuroQol 5 Dimensions (EQ-5D-5L), evaluated at 3, 6, and 12 months, compared with baseline. VEINES-QoL/Sym scoring was based on the intrinsic scoring method.²¹ Ulcer healing and reduction in venous ulcer area were evaluated for C6 patients (using the Swift visual application²²), and ulcer recurrence was evaluated for C5 and healed C6 patients.

VenoValve safety

Major adverse events (MAEs) consisting of major bleeding, deep wound infection, ipsilateral DVT, pulmonary embolism, and mortality were captured. The primary safety end point was the composite of MAE within 30 days of surgery. Secondary safety end points were MAE beyond the perioperative period, as well as any serious adverse event affecting patient health regardless of device implantation (Supplementary Table, online only).

Statistical analyses

The incidence of a greater than 30% improvement in duplex-derived reflux time was evaluated against a prespecified performance goal of 55%, derived from literature in which open surgical valve reconstruction was used for the treatment of a similar patient population. Based on the review, the mean rate of the primary effectiveness end point was 54.8%, which was rounded up to 55% for the effectiveness performance goal for the current study.

Assuming an attrition rate of 10% through 6 months, enrollment of 75 patients was expected to provide 67 evaluable patients and 90% power, assuming the expected success rate of 91% with a performance goal of 55% for reflux time. Nominal P values were calculated for changes from baseline in rVCSS, pain, VEINES, and EQ-5D-5 L, with no formal hypothesis testing or correction for multiple observations. As Shapiro-Wilk testing found non-normal distributions of change in some instances, P values both for student t testing and Wilcoxon signed rank testing were calculated. A P value of less than .05 was considered statistically significant.

Results

Patients and procedural characteristics

Between September 2021 and September 2023, 166 patients were screened and 75 were enrolled in the study across 23 clinical sites in the United States (Appendix 4, online only). The median age was 65 years (interquartile range, 57-70 years) and 16 patients (21.3%) were Black, Hispanic, or Latino (Table I). Most had a history of smoking (56%) and diabetes was prevalent in the group (30.7%). Ten patients had chronic kidney disease (13.3%) and 11 had peripheral neuropathy (14.7%). Patients presented with CVI C4b (6.7%), C4c (6.7%), C5 (28.0%), or C6 (58.7%) disease. The majority of patients with C6 disease (75%) had nonhealing ulcers for a period of more than 1 year. The etiology of CVI was post-thrombotic for most patients (74.7%).

Table I.

Baseline characteristics of patients enrolled in Surgical Antireflux Venous Valve Endoprosthesis (SAVVE)

Characteristic	All patients (n = 75)
Age, years	65 (38-83)
Male sex	61 (81.3)
Race
White	65 (86.7)
Black or African descent	9 (12.0)
Unknown or declined to state	1 (1.3)
Hispanic or Latino Ethnicity group	7 (9.3)
Body mass index	32.7 (27.3-36.2)
Post-thrombotic	56 (74.7)
rVCSS	17 (5-27)
CEAP clinical classification
C4 (b or c)	10 (13.3)
C5	21 (28.0)
C6	44 (58.7)
Active ulcer duration (C6 patients only)
≤1 year	11 (25.0)
Not healed for >1 year	33 (75.0)
History of smoking	42 (56.0)
Current	9 (12.0)
Former	33 (44.0)
Diabetes	23 (30.7)
Peripheral neuropathy	11 (14.7)
Chronic kidney disease	10 (13.3)
Coronary artery disease	6 (8.0)

CEAP, Clinical-Etiology-Anatomy-Pathophysiology.

Values are median (range) or number (%).

A total of 73 patients were successfully implanted with the bioprosthetic valve. Fifty-three patients received a 9-mm VenoValve and 20 patients received a 10-mm VenoValve. A bovine pericardial patch angioplasty was used to assist vein closing for 11 patients (Fig 2). In this (implanted) group, the median baseline reflux time was 3048 ms. The median rVCSS score at baseline was 16 on the 30-point scale.

Fig 2.

Bovine pericardial patch use for closure of venotomy. The VenoValve (arrow) in the femoral vein with closure having partial tension (A). Bovine pericardial patch angioplasty (arrow) to ensure closure without tension (B). The vein is stretched for closure and closed snug around the valve to avoid paravalvular reflux.

Patency

Intraoperative device patency was 100% (73 patients). Device patency and functionality at 12 months were 98.4% (63 of 64) and 96.2% (50 of 52), respectively. Technical success, defined as no occlusion or serious device-related adverse events through 30 days, was achieved in 64 of 73 patients (87.7%). Two patients could not be implanted owing to procedural difficulties mobilizing the femoral vein (eg, owing to scarring). The devices became occluded in three patients (two also had ipsilateral DVTs, for which one had the device explanted within 24 hours), and nine other patients had ipsilateral DVTs. DVTs resolved without sequelae. Six of the DVTs were resolved within 6 months. One additional DVT was resolved by 1 year. At 1 year, one DVT had residual post-thrombotic scar tissue and one had a status unknown.

Venous reflux

Follow-up at 6 months was completed for 70 of 73 patients (95.9%; 1 patient withdrew and 2 were lost to follow-up). A decrease of 30% or more in duplex-derived popliteal reflux time at 6 months was observed in 23 of the 67 patients (34.3%) with evaluable data. Median improvements relative to baseline in duplex-derived popliteal reflux time were 20.5% at 30 days, 12.4% at 3 months, 13.2% at 6 months, and 18.5% at 12 months.

Clinical end points

Analyses of rVCSS showed a clinically meaningful benefit (≥3 points) in 50 of 70 patients at 3 months (71.4%), 52 of 70 patients at 6 months (74.3%), and 55 of 65 patients at 12 months (84.6%) (Fig 3). Among responders, the average improvement in rVCSS was 5.4 points at 3 months, 6.9 points at 6 months, and 7.9 points at 12 months. Compared with baseline, including all evaluable data for all patients in the study, there was a 4.9-point improvement in mean rVCSS at 3 months (P < .001), a 5.9-point improvement at 6 months (P < .001), and a 6.7-point improvement at 12 months (P < .001) (Fig 4).

Fig 3.

Percentage of patients with clinically meaningful improvement in disease severity (≥3 points on the Revised Venous Clinical Severity Score [rVCSS]) after implantation of the VenoValve.

Fig 4.

Mean Revised Venous Clinical Severity Score (rVCSS) at 3, 6, and 12 months after implantation of the VenoValve compared with baseline.

Post hoc analysis of rVCSS revealed that improvements in scores occurred across multiple categories and were not due to isolated changes in a single category. Among the 55 patients with improvement of 3 or more points at 12 months, 55 (100%) showed an improvement in at least two rVCSS categories, 53 (96%) showed an improvement in at least three rVCSS categories, 40 (73%) showed an improvement in at least four rVCSS categories, and 34 (62%) showed an improvement on at least five rVCSS categories (Appendix 5, online only).

Quality-of-life end points

Compared with baseline, VAS data showed statistically significant improvements in median pain ratings at 3 months (60%; n = 57; P < .001), 6 months (76.7%; n = 62; P < .001), and 12 months (74.7%; n = 54; P < .001). VEINES-Sym scores improved on average by 18.2 points (median, 17.0 points), 16.4 points (median, 13.0 points), and 16.3 points (median, 13.0 points) at 3, 6, and 12 months, respectively. VEINES-QOL scores improved on average by 17.2 (median, 13.0), 18.1 (median, 15.0), and 15.7 (median, 14.0) at 3, 6, and 12 months, respectively. All VEINES score improvements were statistically significant relative to baseline (P < .001) (Fig 5). The median change from baseline at 3, 6, and 12 months in the EQ-5D-5L index score showed improvements of 40.0%, 43.5%, and 37.2%, respectively (all P < .001).

Fig 5.

Quality of life assessments at 3, 6, and 12 months after implantation of the VenoValve. (A) VEINES-Sym. (B) VEINES-QOL.

Reduction in venous ulcer area

Forty-three treated patients had 61 active venous ulcers (C6). Overall, 84% of the venous ulcers healed or improved, with 91.6% of the ulcers of less than 12 months in duration fully healed, and 77.8% of the ulcers of more than 12 months in duration healed or improving (with a 30.6% full healing rate for ulcers >1 year in duration). Changes in venous ulcer healing over time are presented in Table II. Of the 21 patients entering the study classified as C5, two patients (9.5%) experienced recurrence of ulcers that had healed during the study.

Table II.

Changes in venous ulcer healing over time among patients with C6 disease

Months	All C6 (43 patients, 61 ulcers)		C6 ulcer duration subgroups
			≤12 months (10 patients, 13 ulcers)		>12 months (33 patients, 48 ulcers)
	No. of ulcers	% Change in area	No. of ulcers	% Change in area	No. of ulcers	% Change in area
3	47	70.6 [20.9-100]	11	100 [97.5-100]	36	60.4 [4.4-100]
6	50	74.4 [41.4-100]	12	100 [100-100]	38	50.3 [36.3-92.2]
12	47	86.6 [44.3-100]	12	100 [100-100]	35	76.2 [12.3-100]

Values are median percentage decrease in surface area of ulcers [interquartile range].

Adverse events

No unanticipated adverse device-related events were reported. Within 30 days of implantation, MAEs included 9 ipsilateral DVTs (12%), 12 surgical bleeding in 11 patients (14.7%), and 7 surgical site infections (9.3%). There were four other nonsurgical bleeding events. The MAE was 30.7% (28 events in 23 patients) at 30 days. Ninety-three percent of patients who experienced a MAE went on to experience a clinical meaningful benefit (≥3 point rVCSS improvement). No perioperative deaths occurred or pulmonary embolism. One patient died 112 days post procedure owing to a viral illness unrelated to the study or treatment (Supplementary Table S1, online only).

Discussion

This prospective study enrolled a very complex patient population with severe CVI (CEAP classifications C4b-C6) owing to deep valvular reflux who had already failed conventional standard of care treatment. Patients with active ulcers had already exhausted all therapies including superficial vein ablation, and venous outflow obstruction when indicated with 75% having ulcer duration of more than one year and no other option for treatment. Eighty-five percent of enrolled patients experienced a clinically meaningful benefit (≥3-point improvement in rVCSS) at 1 year compared with baseline, with an average rVCSS improvement among the responder cohort of 7.9 points. Implantation of the bioprosthetic venous valve device into the femoral vein successfully performed in 73 of 75 patients (97.3%), and meaningful improvements in disease severity and quality of life were shown across all enrolled CEAP classes, regardless of MAE.

The first-in-human study of the VenoValve among 11 patients with class C5 or C6 disease showed promising results, including a clinically meaningful mean improvement of 8 points on the rVCSS and an average pain improvement of 76% as measured by VAS at 1 year compared with baseline.¹⁷ Follow-up of these patients at three years has recently been reported and continues to demonstrate a sustained improvement in rVCSS scores with 7-point reduction compared with baseline among these complex patients similar to preliminary results of the SAVVE trial that continue to be collected.²³ Even though the pilot study demonstrated a sustained decrease of 62% in mean popliteal vein reflux time, the SAVVE trial did not show similar results. It is possible that variations in imaging techniques between different centers may have contributed to this finding. Alternatively, the presence of collaterals in the majority of patients with post-thrombotic pathology could have provided escape mechanisms for blood to reflux through smaller channels. However, the volume of blood through collaterals is likely much smaller and would generate less venous hypertension after implantation of the VenoValve in the femoral vein. The authors hypothesize that, through this mechanism, reflux time may not decrease substantially however a significant reduction in refluxing blood volume may lead to a decrease in venous hypertension. Similar observations of discordance of reflux time and severity of CVI have been reported in studies examining superficial venous reflux in the great saphenous vein.²⁴ Regardless of the results of popliteal vein reflux, the results of this trial demonstrate decreases in disease severity and pain with consistent and sustained improvement in patient-reported outcomes. The therapeutic potential of this approach is promising in that meaningful improvements were observed in a clinically relevant real-world (and increasing) population across all enrolled CEAP classes, including many C6 patients, of whom nearly one-third had diabetes, and with an average body mass index in the range of class 1 obesity.

CVI from deep venous reflux is underestimated, underdiagnosed, and undertreated. In its most severe form, it causes venous leg ulcers, the most prevalent type of leg ulcer, accounting for up to 80% of leg ulcers among patients with chronic venous disease.²⁵ Even though effective modalities to treat superficial venous reflux and deep venous outflow obstruction are available, patients with venous ulcers in the presence of deep venous reflux can have a lifetime struggle with compression therapy and local wound care as demonstrated by the majority of patients with C6 having ulceration for more than a 1-year duration. The implantation of the VenoValve provided significant improvement in clinical end points and patient reported outcomes commensurate with vein ablation of the great saphenous vein and iliac vein stenting in patients with superficial reflux and outflow obstruction, respectively. In the recent SAPTAP trial, patients with varicose veins treated with phlebectomy and vein ablation demonstrated a 10-point improvement in the VEINES-QOL and VEINES-Sym after 12 months.²⁶ In contrast, Morris et al²⁷ examined the quality of life for patients undergoing venous stenting for chronic venous disease and demonstrated a 20-point increase in VEINES-QOL and VEINES-Sym that was sustained for up to 3 years. Those findings were reproduced in the VIVID trial using the Duo venous stent system.²⁸ Thus, the 16.3 points and 15.7 points improvement in VEINES-Sym and VEINES-QOL, respectively, fall within the expected benefit for various treatment modalities for CVI and confirms a new modality to treat patients with no other surgical options.

The MAE rate was driven predominantly by bleeding events likely related to early initiation of full anticoagulation after surgery (within hours) in an inflamed, frequently post-thrombotic surgical bed with venous hypertension. Most important, there was no mortality in the perioperative period or pulmonary embolism and 94% of patients derived a significant benefit from surgery by achieving a clinically meaningful improvement in rVCSS. The MAE in the SAVVE trial represent an improvement compared with the pilot study that showed 40% MAE in the perioperative period (two bleeding, two infections).¹⁷ Additional refinements in the surgical algorithm for closure, hemostasis, and postoperative anticoagulation could decrease the bleeding rate and complications further in the future. In contrast, alternative endovascular technology is being developed and could mitigate the risk of bleeding by avoiding surgical incisions specifically in patients deemed to be high risk for bleeding.

Even though it was prospective, the SAVVE trial is limited by the absence of a comparative group and, therefore, selection bias is difficult to assess. In contrast, the use of venoactive medications, compliance and grade of compression therapy, and details of wound care in patients with ulceration were not controlled for before and after surgery and could be confounding factors for the results of the study. Further research is needed to better understand the link between objective hemodynamic measures and clinical status. It is likely that reflux time is not the optimal measure to assess hemodynamic changes, but alternative methods to assess for pressure could prove to be better. However, the trial design included validated measures for clinical improvement, venous-specific quality of life and symptoms, pain, and both physician-reported and patient-reported outcomes. The benefits of the VenoValve surgery were demonstrated in a relatively small cohort of predominantly white males and further research is needed to confirm similar improvement in females and in patients with racial or ethnic minorities, as well as across the socioeconomical spectrum. All the data from this study support a consistent benefit for a group of patients who most often have been met in clinic with the absence of effective treatment options.

Conclusions

Implantation of the bioprosthetic venous valve yielded significant clinical benefits in patients with severe CVI (CEAP clinical classifications of C4b-C6) even in patients with MAEs. This device could provide a treatment modality for patients with deep venous reflux who are often deemed to have no surgical option.

Author Contributions

Conception and design: Not applicable

Analysis and interpretation: CIOC, EH, CG, MS

Data collection: Not applicable

Writing the article: CIOC

Critical revision of the article: CIOC, EH, CG, MS

Final approval of the article: CIOC, EH, CG, MS

Statistical analysis: Not applicable

Obtained funding: Not applicable

Overall responsibility: CIOC

Funding

This study was designed and funded by EnVVeno Medical.

Disclosures

C.I.O.C. is consultant for SVS-PSO, EnVVeno Medical, has IP of patent U.S.S.N. 10,524,89, and has received research support from Yale department of Surgery, SVS, AVF, CT Innovation, VSGNE, NIH, Boston Scientific, Medtronic, EnVVeno Medical, and Inari Medical. E.S.H. is consultant for EnVVeno, Medtronic, and BD.

From the American Venous Forum and Society for Vascular Surgery