Surgical Treatment of Moderate-to-Severe Post-Thrombotic Syndrome

General Review Surgical Treatment of Moderate-to-Severe Post-Thrombotic Syndrome Rachel T. Bond,1 Jacqueline M. Cohen,2 Anthony Comerota,3,4 and Susan R. Kahn,2,5,6 Montreal, Quebec, Canada; Toledo, Ohio; and Ann Arbor, Michigan

Background: Severe post-thrombotic syndrome (PTS) occurs in 5% to 10% of patients after deep venous thrombosis. Medical therapy such as compression has limited effectiveness for the treatment of such patients. The objective of this study was to systematically review the effectiveness and safety of surgical approaches for the treatment of moderate-to-severe PTS. Method: A computerized search was conducted using PubMed and reverse citation searches to retrieve English- and French-language articles, published after 1980, reporting on the endovascular and surgical treatment of PTS. Results: Three hundred three titles were retrieved, of which 28 full publications were reviewed. Twelve articles met criteria for inclusion, reporting on 349 patients. Surgical techniques included vein dilation and stent placement (two studies), venous bypass grafting (two studies), endophlebectomy with reconstruction (one study), valve reconstruction/transplant (six studies), and interruption of perforating veins (one study). Follow-up periods ranged from 1 month to 5 years. Eleven of 12 included studies described improvement in PTS after the given surgical intervention. Seven of 12 studies found improvement in all anatomic measures assessed (e.g., venous valve competency and patency, venous filling times, or ambulant venous pressure), and 11 of 12 studies reported clinical improvement (e.g., improvement in signs and symptoms, ulcer healing, ability to return to work, or reduced need for elastic compression stockings), with rates of ulcer healing ranging from 50% to 100%. Eight of 12 studies (representing 264 patients) reported safety outcomes. Complications reported most frequently were hematoma/seroma formation and wound infection, with no reported instances of mortality or pulmonary embolism. Limitations of the studies included a lack of randomized controlled trials, absence of control groups, small sample sizes, short follow-up periods, retrospective data collection, imprecise definition of PTS, heterogeneity of study participants, and, in three studies, lack of reporting on procedure safety. Conclusion: Surgical and endovascular treatment of moderate-to-severe PTS could have the potential to be effective where conservative and medical treatments have failed. Our review describes studies of surgical techniques to treat PTS, but highlights important limitations of such studies. Further research using stricter research methodology is needed to evaluate the potential role of surgical techniques for the treatment of moderate-to-severe PTS.

1

Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

2

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada. 3

Division of Vascular Surgery, Jobst Vascular Institute, Toledo, OH.

4

Division of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, MI. 5 Division of Internal Medicine, McGill University, Montreal, Quebec, Canada. 6 Division of Internal Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.

242

Correspondence to: Susan R. Kahn, MD, FRCPC, MSc, Division of Internal Medicine, McGill University, and Center for Clinical Epidemiology, Jewish General Hospital, 3755 Cote Ste. Catherine, Room H420.1, Montreal, Quebec H3T 1E2, Canada; E-mail: susan.kahn@ mcgill.ca Ann Vasc Surg 2013; 27: 242–258 DOI: 10.1016/j.avsg.2012.04.004 Ó 2013 Elsevier Inc. All rights reserved. Manuscript received: May 20, 2011; manuscript accepted: March 1, 2012; published online: July 2, 2012.

Vol. 27, No. 2, February 2013

INTRODUCTION The post-thrombotic syndrome (PTS) is a constellation of signs and symptoms, including pain, swelling, heaviness, paresthesia, erythema, and leg ulcers.1 It occurs in 20% to 50% of patients after a deep venous thrombosis (DVT), making it the most frequent complication of DVT.1 PTS is moderate2 in 10% to 15% and severe in 5% to 10% of patients, and owing to its chronic course, it is burdensome to patients and costly to society.3 The pathophysiology of PTS involves venous valvular reflux and persistent venous obstruction.4 Calf muscle pump dysfunction can be a contributor to PTS, especially in patients with limited ankle mobility. Management of PTS typically includes the use of medical therapy such as compression stockings or devices3 and, less often, venoactive drugs,4 or antithrombotic and profibrinolytic agents.5 Less frequently, surgical or endovascular treatment of PTS is attempted when conservative treatment has failed to control severe manifestations of the condition, such as chronic pain, intractable limb edema, and venous leg ulcers.3 Surgical treatments for PTS have been described since the 1950s, first using ligation of pathologic veins, sympathectomy, and skin grafting in an attempt to control the swelling and ulcers of PTS.6,7 Later, iliac vein obstruction was treated by using a saphenous vein for a femorofemoral venous bypass, as described by Palma and Esperon in 1960,8 and direct venous valve reconstruction for vascular incompetence, as described by Kistner in 1968.9 Over the ensuing years, several additional surgical methods have been developed, including valvuloplasty, vein and valve transplantation, and transposition.10 The studies describing these techniques have often lumped patients with minor chronic venous insufficiency (CVI) together with patients with confirmed PTS, and have quoted success rates ranging from 40% to 70%.10,11 To better define the types of populations studied, the procedures performed, and the outcomes obtained, we performed a systematic review of the literature on the effectiveness and safety of surgical and endovascular treatments for moderate-tosevere PTS.

MATERIALS AND METHODS A computerized search was conducted using PubMed to retrieve English- and French-language articles reporting on the surgical or endovascular treatment of PTS from 1980 until June 2010.

Treatment of moderate-to-severe PTS

243

Various combinations of the search terms postthrombotic syndrome and post-phlebitic syndrome were combined with one or more of the following search terms: surgery, surgical treatment, stent, stenting, percutaneous, angioplasty, balloon dilation, bypass graft, valve repair, valve transposition, valve reconstruction, and intervention. After the initial PubMed search, the reverse citation search engines ISI Web of Science and Scopus were used to retrieve all articles that referenced the initially retrieved articles, and these titles were reviewed as well. Additionally, one article that was not retrieved in the initial search was identified by a colleague as pertinent and included. Retrieval and review of articles was restricted to clinical studies in humans that described outcomes after a single surgical technique or an endovascular procedure was performed in patients with confirmed PTS. Articles were excluded if they were review articles, included patients who had CVI and not PTS, or if combinations of multiple surgical techniques that differed among study participants were used, such that the effects of a single surgical technique could not be determined. Studies where the authors claimed that participants had moderate or severe PTS by either the CEAP (clinical, etiologic, anatomic, and pathophysiologic) or Kistner classification but did not clearly define PTS were included in the review. Owing to the diversity in patient populations, surgical techniques, and outcomes reported across retrieved studies, pooling of data and performance of a meta-analysis was neither feasible nor considered to be methodologically appropriate. Hence, we did not attempt to calculate summary statistics but rather present our results descriptively.

RESULTS Study Characteristics A total of 303 titles were retrieved (300 from the PubMed search, two from reverse citation searches, and one identified by a colleague), of which 28 publications were reviewed in full. The 275 articles initially excluded were titles that were found on the initial PubMed search but clearly, based on the title and abstract alone, did not discuss surgical treatments of PTS. Some were obviously discussing CVI and others discussed grossly unrelated topics. A flow diagram of how titles identified were considered for inclusion in our review is shown in Figure 1. Twelve articles (nine prospective and three retrospective cohort studies) were identified that met criteria for inclusion in our review (Table I).12e23 Seven were single-center studies12,13,16,18,19,21,23

244 Bond et al.

Annals of Vascular Surgery

Fig. 1. Titles identified by our search strategy and algorithm for inclusion in review.

and five were two-center studies,14,15,17,20,22 and none of the studies included control patients who did not undergo surgery. Patient Characteristics In all, the studies reported on 349 patients, the great majority of whom had failed conservative therapy. Ten of 12 studies12e20,23 classified patients as having advanced grade II PTS, or higher, according to CEAP criteria24; two studies18,22 classified patients as having a history of chronic DVT and grade III or IV

incompetent valves according to the Herman et al. and Kistner classification25,26; and one study21 did not explain how severity of PTS was classified. The aforementioned classifications of PTS, as well as the authors’ description of patients as being in the moderate-to-severe category of PTS, were used to categorize patients’ PTS in the included studies. Six studies13,17e20,23 reported duration of PTS symptoms, with a cumulative range of 1 month to 27 years. Demographic and clinical characteristics of patients were difficult to summarize owing to diverse and incomplete reporting across studies.

Table I. Comparison of studies

Author, yr

Title, study design

Definition of PTS

Patient types, N

Excluded patients

Intervention

Outcomes

Results

Femoral vein cannulation (blind or US-guided) and percutaneous balloon dilation and stenting of iliac vein

Effectiveness: Anatomical outcomes - Intraoperative treatment success defined as 1) <20% residual stenosis compared with maximal expected dilation, and 2) elimination of venous pressure gradient - Postoperative treatment failure defined as occlusion of stent on phlebography Clinical outcomes - Pain evaluated by visual analog scale from 0 to 10 (10 ¼ most severe pain) - Swelling assessed as grade 0 (absent), 1 (pitting, not obvious), 2 (visible ankle edema), 3 (massive edema encompassing entire leg) - Leg ulcers Safety Mortality Postoperative complications (see Results)

Effectiveness: Anatomical outcomes - Postoperative occlusion rates were 6/78 (8%) and technical success rate were 73/78 (94%) Clinical outcomes - Patients free of pain rose from 6% to 60%. Average pain score halved from 4.4/10 to 2.2/10 - Rate of limbs with no swelling increased from 3% to 42% - Average swelling score of 1.6 decreased to 0.9 - 24 limbs had leg ulcers before stenting. 12/24 (50%) healed and did not recur, 3/24 (13%) healed but recurred, 5/24 (21%) never healed, 4/24 (17%) were lost to follow-up Safety - No mortality 0/137 (0%) - Blind cannulation led to one retroperitoneal bleed treated with blood transfusion and one artery injury repaired by insertion of graft - One limb had postoperative swelling despite

Length of follow-up

Potential for bias

Percutaneous interventions (balloon dilation, followed by stent) Neglen et al., 200012

Single-center prospective study

PTS patients had verified Venous post-thrombotic obstruction, disease by known often in previous DVT combination diagnosed with duplex with reflux, or ascending resulting in phlebography, with stasis ulcers, chronic symptoms disabling limb including pain, pain, and swelling, dermatitis/ swelling pigmentation, and without active ulcers. Severity skin changes was classified according to CEAP classification N ¼ 137 (61 with primary disease and 78 with PTS) M ¼ 39, F ¼ 39 Median age ¼ 47 yr (range ¼ 18e77)

Patients with venous obstruction due to local compression from malignant tumor

Some patients had Median previous follow-up surgical in PTS group: interventions 13 mo Some (range ¼ patients on 2e36 mo) At 6 wk, then warfarin before intermittently procedure were (reason not put back on it discussed) afterward, whereas others were not anticoagulated More complications in group without US guidance Phlebograph poor at detecting stenosis (lack of gold standard)

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Table I (continued )

Author, yr

Title, study design

Definition of PTS

Patient types, N

Excluded patients

Intervention

Outcomes

Results

Length of follow-up

Potential for bias

Patient inconsistent in terms of thrombophilia Safety Not discussed No blinding

patent stent that subsided - In one limb, guidewire got caught in stent, necessitating removal of both by venotomy Rosales et al., 201013

Patients in whom Patients with chronic Reflux and/or Single-center post-thrombotic venous occlusions after obstruction in prospective occlusion DVT with open patients after observational extended to the popliteal and distal DVT, study popliteal level, femoral veins with symptoms precluding evaluated by CDU, AVP including adequate blood measurement, AV, VOP, venous flow VPG, and CT venography, claudication or trans-femoral/ and leg popliteal venography. ulceration All patients CEAP 3 to 6 and incapable of functioning at work and/or in other physical activities. Symptoms assessed by VCSS N ¼ 34 M ¼ 15, F ¼ 19 Median age ¼ 41 (range ¼ 15e63)

Venous access was established under US, the occluded segment was passed through using guidewires, predilatation angioplasty was performed, then 16- to 12-mm self-expanding stents were deployed, and then dilated with appropriate size balloons

Effectiveness: Anatomical outcomes - CDU performed to visualize stent segment recording flow and looking for morphological changes suggesting stenosis (>50% diameter reduction) - If CDU inconclusive, venography performed - VOP performed to evaluate early hemodynamic signs of reobstruction Clinical outcomes - Resolution/recurrence of signs and symptoms recorded by VCSS Safety Not discussed

Effectiveness: Anatomical outcomes - Successful recanalization in 32/34 (94%) - VOP and VPG showed outflow impairment in 18/34 (53%) - 4/34 (12%) showed postoperative hemodynamic improvement - 2-yr primary patency rate was 14/21 (67%), primary-assisted patency was 16/21 (76%), and secondary patency was 19/21 (90%) Clinical outcomes - Venous claudication, edema, and pain resolved in those successfully recanalized - 17 had symptoms recurrence - 4/7 (57%) of ulcers healed Safety Not discussed

Median follow-up was 33 mo (range ¼ 1e96) Follow-up at 3, 6, and 12 mo, and then yearly

3-cm to 4-cm segment of involved vein (SF, CF, PF, P, or T)

Effectiveness: Anatomical outcomes

Effectiveness: Anatomical outcomes

Followed at 4- to No blinding 6-mo Procedures intervals performed

Bypass grafting Raju et al., 199914

Two-center retrospective study

Not defined

PTS patients (diagnostic criteria not discussed) with trabeculated

Not discussed

leg veins who failed initial treatment. Indication for surgery was recurrent stasis dermatitis, ulceration, pain, or painful swelling. CEAP classification range C3 to C6 N ¼ 81 patients (83 limbs) M:F, 1:1 Mean age ¼ 53 (no range given)

- Early patency rate - Patency and is cleared of small 78/81 (96%). competence branches, collaterals, Cumulative patency of transferred and intraluminal rate >80% at 10 yr valve assessed by synechiae. Axillary duplex and, sometimes, - At 4 yr, valve closure valve is excised and time 1 sec in 38% contrast venography distended during and 2 sec in 53% - Venous function bench repair, then - Arm/foot venous assessed by arm/foot transferred and pressure technique venous pressure anastomosed to showed 4/64 (6%) technique measuring prepared vein. A patients increased postexercise pressure, polytetrafluoroethylene obstruction grade percentage drop, VFT, sleeve is applied from compensated to VP, and VFI around the decompensated Clinical outcomes transferred valve category (transient in - Complete two patients) epithelialization - VFT (6 sec needed to consider preoperatively and ulcer healed 12 sec postoperatively) - Leg swelling graded as and VFI (6 sec 0 (absent), 1 (pitting, preoperatively and 4 not gross), 2 (visible sec postoperatively) ankle edema), or 3 significantly improved (massive, entire leg) postoperatively, no - Pain evaluated on visual analog scale 0 to change in postexercise pressure 10. A 3/10 decrease or percentage drop considered significant Clinical outcomes improvement - Patients free of ulcer - Use of compression recurrence was 48/77 stockings (62%) at 5 yr, 44/ Safety 77 (57%) at 10 yr, Mortality and 41/77 (53%) at Postoperative 15 yr complications (see - 31/37 (83%) grade 0 Results) or 1 swelling limbs remained stable, 6/37 (16%) worsened - 11/20 (55%) grade 2 or 3 swelling limbs improved and 9/20 (45%) remained stable - Mean pain decreased from 6/10 to 2/10 (P < 0.01). 7/53 (13%) had no preoperative or postoperative pain, 37/53 (70%) had relief of pain, 7/53 (13%) had no change in pain, and

during first yr, then less frequently. In total, patients followed over 10 yr, but mean follow-up time not given

not uniform across participants Mean follow-up time not described

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Table I (continued )

Author, yr

Title, study design

Definition of PTS

Patient types, N

Excluded patients

Intervention

Outcomes

Results

Length of follow-up

Potential for bias

Mean follow-up of 56 mo. Routine interval of follow-up not described

Retrospective Not blinded Small N Clinical outcome criteria not discussed

2/53 (4%) had worse pain - Of 55 patients who reported stocking use preoperatively, 15/55 (27%) abandoned use, 14/55 (26%) used irregularly, and 26/ 55 (47%) used on a regular basis Safety - No mortality - 5/83 (6%) hematoma/seroma formation - 5/83 (6%) superficial wound infection - 2/83 (2%) deep wound infection - 3/83 (4%) DVT (no PE) - 2/83 (2%) miscellaneous complications Cardon et al., 199915

Two-center retrospective study

16 patients with Reflux due to post-thrombotic deep irreversible valvular reflux with valve severe pain preventing destruction normal activity and resulting in treatment-resistant distal ulcers. All CEAP venous grade 3. All had hypertension duplex-confirmed and venous reflux classic extending below the symptoms knee. All had US- and of edema, pain, descending pigment phlebographydeposition, and confirmed ulceration competent GSV N ¼ 16 M ¼ 10, F ¼ 6 Mean age ¼ 56 yr (range ¼ 56e76)

Surgical transposition Patients with of GSV to ipsilateral extensive SFV with end-to-side thrombotic anastomosis and involvement of ligation of SFV to SFV, reflux in avoid diameter DFV visualized mismatch by phlebography, or proven predisposing abnormalities for recurring venous thrombosis were excluded

Effectiveness: Anatomical outcomes - Patency - Competency (both assessed by duplex scanning) Clinical outcomes - Healing of ulceration - Disappearance of pain (measurement not discussed) Safety Mortality Postoperative complications (see Results)

Effectiveness: Anatomical outcomes - 1/16 (6%) bypasses not patent - 3/16 (19%) bypasses not competent Clinical outcomes - 11 patients ‘‘cured,’’ 5 patients ‘‘failures’’ - 9/9 (100%) with recurrent ulceration had healing at 3 mo - 4/16 (25%) had recurrent ulcers - 1/16 (6%) had recurring pain and hyperpigmentation * The four anatomical failures corresponded to three of the clinical failures Safety - No mortality 0/16 (0%)

- No PE 0/16 (0%) - 1/16 (6%) postoperative hematoma requiring surgical drainage - No thrombosis or recurrent phlebitis 0/16 (0%) Endophlebectomy and reconstruction Puggioni et al., 200416

Single-center retrospective study

Not discussed

Patients with advanced post-thrombotic CVI. All had failed conservative management and had disabling symptoms impairing quality of life. Indications for surgery were active or recurrent ulcers, swelling with severe pain, and disabling swelling. All CEAP classification 3 to 6. Deep venous obstruction and reflux sites were confirmed with duplex scans and phlebography N ¼ 13 M ¼ 10, F ¼ 3 Mean age ¼ 52 yr (range ¼ 35e75)

Not discussed

Venotomy through obstructed segment. Synechiae attached to intima removed. Constricting bands released. Reconstruction with valve repair, bypass, or valve substitution

Effectiveness: Anatomical outcomes - Competency of treated segments - Early thrombosis near endophlebectomy site Clinical outcomes Ulcer healing Safety Postoperative complications (see Results)

Effectiveness: Anatomical outcomes - Primary patency was 10/13 (77%) - Early thrombosis in 3/13 (23%) (two of whom had further interventions with success) - Overall secondary patency was 12/13 (93%) Clinical outcomes - Ulcer healing in 9/13 (69%) - No ulcer healing in 1/13 (8%) - New ulcers in 3/13 (23%) Safety - 3/13 (23%) wound hematoma - 2/13 (15%) wound infections - 1/13 (8%) leg cellulitis - 0/13 (0%) PE

No

GSV sectioned and invaginated into deep vein, attached to facing wall, and sutured to create bicuspid valve, allowing centripetal flow, whereas impeding centrifugal flow

Effectiveness: Anatomical outcomes

Effectiveness: Anatomical outcomes:

Mean follow-up time was 10 mo (range ¼ 6e14 mo)

follow-up protocol, but further studies obtained within 1, 6, 12 mo. Mean follow-up 10.8 ±8.2 mo

Not blinded No control subjects Procedure not uniform Definition of PTS unclear No clear follow-up protocol

Valve reconstruction/transplant Plagnol et al., 199917

Two-center prospective study

Thrombosis of the Patients with CEAP class 3 treatment-resistant deep veins of post-thrombotic the lower disease. Doppler and extremities retrograde resulting in phlebography showed changes major femoral vein in vein walls reflux. All had and documented or valve clinically diagnosed degeneration DVT leading to N ¼ 19 patients post-

Not discussed

- Patency was 20/20 (100%) - Patency of constructed - No anatomical valve assessed by abnormality in 5/5 Doppler (100%) of patients - Reflux at follow-up assessed assessed by duplex - Mild reflux in 1/19 - Anatomical (5%) of patients abnormalities of

Small N Not blinded Not controlled Not all participants had previous documented DVT Short follow-up Not all participants had the same follow-up Clinical outcome

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Table I (continued )

Author, yr

Title, study design

Definition of PTS thrombotic reflux. The syndrome includes trophic complications such as recurrent peripheral ulceration

Maleti et al., 200618

Single-center prospective study

Patient types, N

Excluded patients

Intervention

(20 venotomies) M ¼ 3, F ¼ 16 Mean age ¼ 60 yr (range ¼ 36e79)

Longitudinal or T-shaped Patients excluded Patients with postSignificant venotomy performed. if had thrombotic venous symptoms and Parietal dissection thrombophilia, reflux assessed trophic lesions performed to obtain contraindications (Kistner grade IV that occur as a an intimal flap. The to and CEAP class 6) consequence intima was dissected anticoagulation, using descending of deep venous and a flap was shaped or severely venography. reflux that is to mimic a natural limited All had treatmentprimary in valve. Either bicuspid ambulation resistant ulcers or etiology. This or monocuspid valves frequent ulcer primary were created recurrence. US scanning etiology and ascending/descending is most venography used to commonly assess if other surgical PTS (not options possible defined N ¼ 16 (18 limbs) further) M ¼ 8, F ¼ 8 Mean age ¼ 60 (range 36e79)

Outcomes

Results

venous system assessed by phlebography Clinical outcomes - Ulcerated lesions (measurement not discussed) - Edema (measurement not discussed) Safety - Postoperative complications (see Results)

Clinical outcomes - Ulcerated lesions healed within 1 to 6 mo. (N not discussed) - Persistent edema seen in 2/19 (11%) of patients Safety - 3/19 (16%) subcutaneous hematoma (one required puncture drainage) - 2/19 (11%) lymphocele (one required puncture drainage) - 1/19 (5%) transient dysesthesia on anterior aspect of thigh

Effectiveness: Anatomical outcomes - Venous patency and neovalve competence were assessed clinically and with US. Competency achieved when reflux below reconstruction site <1 sec - VFI, RT, and EF variations assessed by APG Clinical outcomes Ulcer healing (subjectively assessed) Safety Mortality Postoperative complications (see Results)

Effectiveness: Anatomical outcomes - Early patency was 16/18 (89%). Two limbs had early thrombosis below neovalve site, but both had complete recanalization at 1 yr - Patency at 1 yr was 17/18 (95%) - Valve competence deterioration was 0/17 (0%) - Statistically significant improvement (P < .001) in VFI, EF, RT Clinical outcomes - Ulcer healing in 16/18 (88.8%) - Ulcer recurrence in 0/18 (0%) Safety - 0/16 (0%) mortality rate - 1/16 (6%) wound hematoma

Length of follow-up

Potential for bias measures not discussed

Patients had Median differing follow-up comorbidities, was 22 mo including HTN, (range ¼ DMII, HCV, 1e42 mo). CRF, IBD Duplex Some patients scanning had bicuspid occurred at 1 and others had and 6 mo and thereafter monocuspid valves at 1-yr constructed intervals No control subjects PTS poorly defined Clinical outcome measures subjectively assessed

- 2/16 (12%) seromas - 0/16 (0%) wound infection - 0/16 (0%) PE - >50% had subcutaneous hardening of lymphatic origin, but was transitory in all situations Neglen and Raju, 200319

Not discussed Prospective single-center study

Not discussed Patients with postthrombotic disease with active venous stasis ulcers (20 patients), severe post-thrombotic pain and lipodermato-sclerosis or stasis dermatitis (five patients). 20/25 limbs had previous venous procedures. All had marked deep venous reflux determined by APG, duplex Doppler scanning, and venography. All patients were CEAP class 4 to 6 N ¼ 25 (27 valves transplanted) M ¼ 17, F ¼ 8 Median age ¼ 44 yr (range ¼ 32e88)

Cryopreserved venous valve allografts were inserted as salvage procedure after other methods of valve reconstruction were unavailable or exhausted. End-to-end anastomosis performed

Effectiveness: Anatomical outcomes - Valve patency observed with duplex Doppler scanning or ascending venography - Incompetence of vein segment defined as duration of reflux >0.5 sec Clinical outcomes - Ulcer healing defined as complete re-epithelialization - Pain measured on visual analog scale from 0 to 10 - Swelling defined as grade 0 (absent), grade 1 (pitting, not obvious), grade 2 (visible ankle edema), grade 3 (massive, entire leg) Safety Mortality Postoperative complications (see Results)

Effectiveness: Anatomical outcomes - Patency and competency in 21/25 (84%) - 11/27 (41%) of implants occluded - 7/27 (27%) of valves were both competent and patent at 24 mo - 0/16 (0%) showed hemodynamic improvement in functional tests Clinical outcomes: - 11/22 (50%) were ulcer free - 0/22 (0%) with pain had a significant difference in pain score - 0/25 (0%) had a decrease in swelling Safety - 0/25 (0%) mortality - 12/25 (48%) wound complications - 2/25 (8%) superficial wound infection (required antibiotics) - 1/25 (4%) cellulitis (required antibiotics) - 4/25 (16%) deep wound infections (required surgical drainage) - 3/25(12%) large seromas (required surgical drainage) - 1/25 (4%) wound hematoma (required surgical drainage)

Not all valves Patency and inserted into competency same veins follow-up: No control group median 11 mo (range ¼ Bench repair to valves not 1e41 mo) uniform across Clinical patients follow-up: median 20 mo (range ¼ 2e49 mo)

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Table I (continued )

Author, yr

Title, study design

Definition of PTS

Patient types, N

Excluded patients

Intervention

Outcomes

Results

Length of follow-up

Potential for bias

- 1/25 (4%) acute rejection of transplant requiring explantation Bry et al., 199520

Prospective two-center study

Nash, 198821

Prospective Not discussed single-center study

Not discussed

Patients with postthrombotic CVI with advanced stage II or III disease by Kistner scoring. All failed prolonged courses of medical therapy. DVT documented in nine patients. Ascending phlebography confirmed post-thrombotic recanalization in all patients. Venous refill time considered abnormal by photoplethysmography in all patients N ¼ 15 M ¼ 12, F ¼ 3 Mean age ¼ 53 yr (range ¼ 30e69)

Excluded if found 5- to 6-cm segment of axillary vein to have a containing one valve hypercoagulable tested for competence state and harvested. Short segment of popliteal vein excised and axillary vein segment interposed in the above-knee popliteal vein. Patency and competency assessed with Doppler

Effectiveness: Anatomical outcomes - Valve patency and competency determined by ascending and descending phlebography - Hemodynamic Evaluation used Photoplethysmography to assess VRT, duplex for venous reflux, APG for VFI Clinical outcomes: - Time to ulcer healing - Leg pain - Edema - Skin nutrition e Lipodermatosclerosis (measurement not discussed) - Ulcer recurrence defined as any loss of epithelial integrity - Ability to return to work Safety Not discussed

Effectiveness: Anatomical outcomes - Patency was 15/15 (100%) - VRT was 17.4 sec - 3/10 (30%) were below mean EF for patients with stage III disease - 1/10 (10%) VFI in normal range - 4/10 (40%) RVF in normal range - 0/10 (0%) valve closure time in normal range Clinical outcomes - Average time to ulcer healing was 55 d - 15/15 (100%) had relief of pain - 13/14 (92%) had relief of edema - 13/14 (92%) were able to return to work or household duties - 5/8 (62%) were free of ulcer recurrence at late follow-up (>4 yr) Safety Not discussed

Average follow-up 5.3 yr (range ¼ 1.25e11 yr)

Noninvasive hemodynamic testing not done preoperatively, so postoperative data compared with data in the literature Small sample size No control intervention Quantification of clinical outcome not discussed Safety of procedure not discussed

Patients with previous deep vein thrombosis identified by Doppler or venography. 17 patients had recurrent ulceration and 6 had severe preulcer skin damage (subjectively measured). 20 had

Not discussed

Effectiveness: Anatomical outcomes

Effectiveness: Anatomical outcomes:

Patients followed at regular intervals (length not specified) and at 12 and 18 mo

No control group Many subjective outcome measures Not all patients received the same follow-up Safety of intervention

5 cm segment of vein containing popliteal valve removed and 5cm segment of brachial vein containing a competent valve was anastomosed to popliteal site

- Valve patency and competency measured by Doppler or venography

- 6/23(26%) had recurrent veins with retrograde flow, but all were controlled with sclerosants

- AVP (measurement technique not discussed) - VRT (measured by Doppler) Clinical outcomes - Ulcer healing - Patient report of pain and comfort - Swelling (measurement criteria not discussed) - Improvement in skin damage (subjectively measured) Safety Not discussed

apparently adequate perforating vein surgery N ¼ 23 (patient gender and age not available)

Taheri et al., 198222

Prospective two-center study

Not discussed All patients had A syndrome in previous deep vein which a thrombosis. All had thrombus in stasis ulceration or main veins disabling leg pain results in (assessment venous stasis, not discussed). 10/13 had valvular previous vein ligation incompetence, and stripping. All had increasing failed supportive venous management. pressure, and Descending symptoms venography ,including assessed all as having leg pain, night incompetent valves of cramps, Kistner grade III to IV venous

A segment of SFV 4 cm below the PF is excised and a 2-cm segment of brachial vein containing a valve tested for patency and competency is transplanted and anastomosed to that site

Effectiveness: Effectiveness: Anatomical outcomes Anatomical outcomes - Valve patency and - Patency of 13/13 (100%) reflux (Kistner - 1/13 (8%) had grade grade 0 to 4) 0 reflux, 8/13 (62%) measured by had grade 1 reflux plethysmography, photoplethysmography, Clinical outcomes and venography Clinical outcomes

- Ulcer healing

not discussed

- 23/23 (100%) patency, but 5/23(22%) had evidence of reflux - 19/23 (83%) had falls in AVP (average of 16 mm Hg) - Fall in AVP persisted for 15/23 (65%) of patients, but rose to near preoperative levels in 4/23 (17%) patients - VRT rose in 10/12 (83%) patients in whom it was recorded at follow-up Clinical outcomes: - 15/17 (88%) patients with ulcers that healed - 1/17 (6%) ulcers remained unhealed - 1/17 (6%) ulcers recurred - 1/17 (6%) patients developed an ulcer at a different site - 23/23 (100%) of patients reported decreased or no pain, increased comfort, and less swelling - 6/6 (100%) patients with skin damage showed rapid improvement Safety Not discussed Every 4 mo for 1 yr

Small N No control intervention Some subjective clinical outcome measures Short follow-up period Safety of intervention not discussed

- Stasis ulcers healed in 6/10 (60%) patients with preoperative ulcers (continued on next page)

Table I (continued )

Author, yr

Title, study design

Definition of PTS

Patient types, N

Excluded patients

Intervention

N ¼ 13 (15 limbs) claudication, edema, and/or M ¼ 7, F ¼ 6 Mean age ¼ 53 yr stasis (range ¼ 27e72) ulceration

Outcomes

Results

- Symptoms resolving (subjectively measured) Safety Not discussed

- 13/13 (100%) reported a considerable decrease in symptoms - 3/11 (27%) reported minimal edema Safety Not discussed

Effectiveness: Anatomical outcomes Correct interruption of incompetent perforator veins identified by echo Clinical outcomes Ulcer healing Return to normal activity Safety Postoperative complications (see Results)

Effectiveness: Anatomical outcomes Doppler results not discussed Clinical outcomes - Mean ulcer healing time was 4.12 weeks - 8/8 (100%) ulcer healing rate - 0/8 (0%) ulcer recurrence - 16/16 (100%) returned to normal activity in 10 to 30 d Safety - 1/16 (6%) formed a hematoma - 3/16 (19%) had l eg edema

Length of follow-up

Potential for bias

Division of incompetent perforator veins Vettorello, Prospective Post-thrombotic 200423 single-center events in the study legs and deep and perforator vein insufficiency leading to CVI and venous ulceration

Patients with a history of previous DVT, chronic ulcers, and CEAP class 5 or 6 N ¼ 16 M ¼ 7, F ¼ 9 Mean age ¼ 61 yr (no range given)

Patients without DVT, ulcers, on anticoagulant therapy, and with infected ulcers were excluded

Interruption of perforator veins to area of previous DVT (identified by echo Doppler) is performed. Nonabsorbable mesh is transferred under fascial layer to cover perforating vein area

Range ¼ 6 to 38 Doppler mo (mean ¼ follow-up 23.2 mo) results not discussed in the articles No control intervention Small sample size Quantification of clinical outcomes not discussed

PTS, post-thrombotic syndrome; DVT, deep vein thrombosis; N, number; M, male; F, female; US, ultrasonography; CDU, color duplex ultrasonography; AVP, ambulant venous pressure; AV, ascending venography; VOP, venous occlusion plethysmography; VPG, venous pressure gradient; VCSS, venous clinical severity score; SF, superficial femoral; CF, common femoral; PF, profunda femoris; P, popliteal; T, tibial; VFT, venous filling time; VP, valsalva pressure; VFI, venous filling index; PE, pulmonary embolism; GSV, great saphenous vein; SFV, superficial femoral vein; DFV, deep femoral vein; EF, ejection fraction; RT, reflux time; APG, air plethysmography; HTN, hypertension; DMII, diabetes mellitus type II; CRF, chronic renal failure; HCV, hepatitis C virus; IBD, inflammatory bowel disease. Herman and Kistner classification of valvular function: grade 0, competent valves with no reflux of dye beyond the upper femoral vein; grade I, minimal incompetence with reflux not beyond the proximal aspect of the thigh; grade II, mild incompetence with reflux into the femoral vein to the level of the knee; grade III, moderate incompetence with reflux just below the knee; and grade IV, severe incompetence with reflux to the calf veins.

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Eleven studies12e20,22,23 reported participant age. No summary mean could be calculated because some studies reported mean, whereas others reported median; however, age across studies ranged from 15 years to 88 years. The same 11 studies reported participant gender, with 52% of participants being male and 48% being female. The reporting of use of previous conservative management and surgical interventions was unclear. Six of 12 studies14,16e18,20,22 clearly reported that all participants had failed medical management. The remaining six studies12,13,15,19,21,23 reported that some participants had previous operative procedures, some had failed medical management, and some had used compression stockings; however, it was not specified whether all patients had previously used one or more type of therapy or if some participants were completely therapy naı¨ve. Five of 11 studies12,13,15,18,19 reported on other patient characteristics and reported a diversity of predisposing factors to thrombosis, including thrombophilia and comorbid medical conditions. Precise quantification of the prevalence of these potentially confounding factors was not provided.

Criteria Used to Define PTS One of the aims of our research was to clearly identify how surgical treatments were used in patients who had confirmed PTS. Across the studies, PTS was defined in diverse ways. Some studies included patients with verified post-thrombotic disease by known previous DVT diagnosed with duplex or ascending phlebography, whereas other studies stated that patients had PTS but did not discuss the diagnostic criteria used. Some authors mentioned that patients had chronic symptoms or signs, including pain, swelling, dermatitis/pigmentation changes, and active and recurrent ulcers, whereas others did not specifically mention symptoms or signs. Ten of 12 studies also reported CEAP scores, a classification schema developed for use in patients with CVI24 that has also been used in some studies of PTS patients.27

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Adjunctive Treatments Used Adjunctive medical and therapeutic treatments differed across studies. All studies, except for one,23 commented on the use of intravenous anticoagulation started during the operative procedure and continued postoperatively between one day to lifelong if the patient was determined to have a hypercoagulable state. Coumadin was used postoperatively in six studies.12,14,17e19,22 One study used a ketorolac injection postoperatively as well as low-dose aspirin indefinitely.12 Mechanical compression devices, including bandages, compression stocking, and intermittent pneumatic compression devices, were used in seven studies.12,14,15,18,20,21,23 The foot of the patient’s bed was raised postoperatively in three studies.15,18,22 Finally, two studies commented on the use of active and passive leg exercises21,22 in the postoperative period. Outcomes Assessed Outcomes used to measure the effectiveness and safety of surgery varied widely across studies. Anatomical outcomes assessed included rates of venous valve competency and patency determined by Doppler ultrasonography or venography. Functional outcomes were assessed by ambulatory venous pressures and venous filling times measured with plethysmographic techniques. Clinical outcomes assessed included improvement in symptoms and signs (e.g., pain, swelling, hyperpigmentation), complete or partial ulcer healing, ability to return to work, and reduced need to use elastic compression stockings. Four studies used a quantitative scoring system to report clinical outcomes,12e14,19 whereas eight studies subjectively reported qualitative change only.15e18,20e23 Safety outcomes reported included surgical site bleeding, vessel injury, hematoma/ seroma formation, infection, DVT, pulmonary embolism, cellulitis, lymphocele, dysesthesia, and acute valve rejection. It was not stated systematically across studies exactly when in the follow-up period these complications occurred and what was the longterm outcome of these complications.

Surgical Techniques Surgical and endovascular techniques used included percutaneous interventions such as vein dilation and stent placement,12,13 venous bypass grafting,14,15 endophlebectomy with reconstruction,16 valve reconstruction or transplant,17e22 and interruption of perforating veins.23 In the 12 studies, duration of follow-up after surgery ranged from 1 month to 5 years.

Effectiveness of Surgery Eleven of 12 studies included for review, representing 324 participants, described anatomic or clinical improvement in PTS after the given surgical intervention.12e18,20e22 Of these, seven studies reported improvement in all anatomic measures assessed,12,15e18,21e23 three reported anatomical improvement in valve competence and patency

256 Bond et al.

but no hemodynamic improvement,13,14,20 one showed no anatomical improvement,19 and one discussed clinical outcomes only and did not quantify anatomical outcomes.23 The same 11 studies also reported clinical improvement over the follow-up period. Four of five studies that assessed pain reported decreased pain levels after surgery, and three of five studies noted a decrease in swelling. All 12 studies assessed ulceration, and all reported ulcer healing after surgery; rates of healing across studies ranged from 50% to 100%. Owing to the varying methods used to report clinical outcomes across the studies and the heterogeneity of surgical techniques, detailed quantitative analysis of symptom improvement across studies, such as weighted average improvement per symptom, was not possible. Safety of Surgery Eight of 12 studies, representing 264 patients, reported safety outcomes.12,14e19,23 No instances of mortality, DVT, pulmonary embolism, or limb loss were reported. Complications reported most frequently were hematoma/seroma formation (reported in seven of eight studies; average incidence: 13%) and wound infection (reported in four of eight studies; average incidence: 11%). One study that examined transplantation of cryopreserved venous valve allografts found no improvement in PTS after surgery and had a complication rate of 12/25 (48%), including deep and superficial wound infections, large seroma formation, cellulitis, hematoma, and acute rejection of transplanted valve.19 Additional detailed results are provided in Table I.

DISCUSSION We systematically reviewed the literature on surgical treatments studied for the treatment of PTS. Five classes of surgical techniques were identified: vein dilation and stent placement, venous bypass grafting, endophlebectomy with reconstruction, valve reconstruction or transplant, and interruption of perforating veins. Of the 12 surgical reports, five studies (procedures) were designed to correct obstruction and seven to correct reflux. Comparisons between studies were difficult because anatomical and clinical criteria and outcomes assessed were not uniform across studies and even within each outcome, the method of assessment and reporting of results differed across studies. Despite the lack of objective quantification of results, eleven of 12 articles reviewed concluded that the surgical technique used showed promise

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in the treatment of PTS, with seven of 12 studies finding anatomical improvement, 11 of 12 studies finding overall clinical improvement, and all 12 studies reporting ulcer healing rates of 50% or more during the follow-up period in comparison with presurgical healing rates. The sole study that concluded that the surgical technique discussed should not be used or researched further investigated the transplantation of cryopreserved venous valve allografts. Cryopreserved venous allografts are prosthetics with immunogenic potential and are associated with poor patency rates when used for lower-extremity arterial revascularization.28,29 Therefore, it is not surprising that disappointing results were observed in the venous system. In this study, the technique was used as a salvage procedure after other surgical techniques had failed. This is different than many other studies reviewed in which the surgical technique discussed was the primary surgical intervention attempted. The aforementioned point limits the potential comparison of this study with the remaining studies; however, it was included because it discussed a surgical technique to treat postthrombotic venous reflux, which is not effective. Methodological limitations of the studies reviewed included a lack of randomized controlled trials, absence of control groups, small sample sizes, short follow-up periods, retrospective data collection, imprecise definition of PTS, heterogeneity of study participants, and a lack of uniform techniques in determining anatomical and clinical outcomes of the techniques used across studies. Some studies used scales to assess clinical improvements, whereas other studies did not explicitly state how clinical improvement was assessed, making it difficult to compare studies or determine the applicability of these studies to the general population. The studies also had limitations in reporting, including lack of reporting with regard to use of anticoagulants and compression stockings, comorbidities and DVT risk factors, and, in three studies, procedure safety. Also, the generalizability of this research is unclear, as all studies were single-center or two-center studies, which may suggest that the procedures can only be performed in highly specialized centers by expert surgeons. Some of the aforementioned limitations bear further discussion. First, the lack of precise definition of PTS in many of the studies prevents us from knowing the heterogeneity of the reviewed population and in what way specific symptoms or personal characteristics of the patients may affect the outcome of the surgical procedure. Moreover, five of 12 studies did not report how PTS was defined.

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This is a major limitation of the research, as we must rely on the authors’ claims that all participants had confirmed PTS and it prevents cross-study comparisons. A barrier to PTS research is the lack of a gold standard test for diagnosis. Six commonly used scales for PTS diagnosis were recently reviewed as part of an international initiative to standardize the diagnosis of PTS. Use of the Villalta scale was recommended, as it takes into consideration signs and symptoms of the disease, is reliable and valid, and was designed specifically for the PTS population.27 None of the articles reviewed used the Villalta scale. Use of this scale in future PTS research would be a useful method to improve the quality of future comparisons and systematic reviews. Second, the lack of control groups in all studies prevents us from being able to conclude whether the long-term effects reported are truly the result of the surgical procedure per se or, alternatively, reflect the natural evolution of PTS over time, or effects of other supportive treatments that may have been used more effectively in postoperative patients but were not explicitly described in the reviewed articles. Third, short postsurgical follow-up periods in many of the reviewed articles prevented conclusions about whether reported effects of the procedures were durable in the long-term and whether significant adverse effects occurred over time. Another important limitation is that the articles published appeared to reflect the procedural interest of the surgeon rather than the needs of the patient. General observations of post-thrombotic patients suggest that venous obstruction is associated with more severe post-thrombotic morbidity than reflux,30 yet seven of the 12 articles addressed only reflux as part of the surgical procedure. It would appear prudent to thoroughly evaluate patients with uncontrolled post-thrombotic morbidity and correct the pathologic component(s) that would lead to the best hemodynamic and, therefore, clinical outcome. Despite the aforementioned limitations, the reviewed articles suggest that there may be a role for surgical and endovascular treatment of moderate-to-severe PTS, and that most of the procedures described (with the exception of salvage transplantation of cryopreserved venous valve allografts) did not result in any serious adverse outcomes. Compression therapy has been shown to be effective to prevent PTS,31 and its use may also offer some benefit for managing symptoms of PTS.32 As current therapies to treat moderate-to-severe PTS are limited,3 randomized controlled studies that compare surgical treatment with medical treatment

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and studies to develop and test new safe and effective surgical procedures are warranted. Interest in the management of patients with chronic venous disease is escalating. There are now objective measures by which patients can be classified,33 their post-thrombotic morbidity quantified,33e35 and their quality of life assessed.36 Future studies evaluating treatment options for PTS should include pretreatment (baseline) assessments and post-treatment outcomes to permit objective measures of patient benefit. Although performance of a formal meta-analysis was not considered to be appropriate for this review, we believe that our article adds to the current literature by describing surgical techniques that have been used to date to treat PTS, summarizing the evidence on their effectiveness and safety, and highlighting gaps in the evidence on surgical approaches to the treatment of moderate-to-severe PTS.

CONCLUSION PTS is a frequent chronic condition for which treatment advances are clearly needed. Surgical treatment of moderate-to-severe PTS to reduce venous valvular reflux and/or improve venous obstruction could have the potential to be effective where conservative and medical treatments have failed. Our review describes studies of surgical and endovascular techniques that have been used to treat PTS, but highlights important limitations of such studies. Further research using stricter research methodology is needed to evaluate the potential role of surgical techniques for the treatment of moderate-to-severe PTS.

Dr. Kahn is supported by a National Investigator (Chercheur National) award of the Fonds de la recherche en sante du Quebec (FRSQ).

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