The clinical and economic impact of chronic venous insufficiency-associated lymphedema and the prevalence of persistent edema after venous intervention

Abstract

Objectives

To determine the demographics, outcomes, and healthcare utilization of patients with chronic venous insufficiency-associated lymphedema (CVI-LED) and the prevalence of lymphedema-specific therapy use after venous intervention.

Methods

The IBM MarketScan Commercial and Medicare Claims Databases were examined for patients with CVI-LED. Patient demographics and the use of lymphedema-specific therapy before and after venous intervention were collected.

Results

Of 85,601 LED patients identified, 8,406 also had a diagnosis of CVI. In the CVI-LED group, 1051 underwent endovenous ablation or venous stent placement. The use of lymphedema-specific therapy before and after venous intervention was 52% and 39%, respectively (p < .05). The mean time of initiation of LED-specific therapy following venous intervention was 265 days after ablation and 347 days after stent placement.

Conclusion

Treating venous hypertension improves certain venous-related signs and symptoms of CVI. However, a significant proportion of patients have persistent edema which may reflect underlying, sub-optimally treated LED.

Keywords

chronic venous insufficiency lymphedema

Introduction

Chronic venous insufficiency (CVI) is recognized as a leading cause of secondary lymphedema (LED).^1,2 CVI is a common though underdiagnosed condition in the United States and throughout the world that requires intense utilization of medical resources.^1,3 CVI results from venous reflux and/or obstruction which may be a sequela of post-thrombotic syndrome secondary to prior deep venous thrombosis (DVT), trauma, venous compression, or superficial venous reflux, among other etiologies. In all causes of CVI, the common end result is venous hypertension variably manifested by edema, claudication, varicose veins, and in advanced cases, venous ulcers.⁴

Hydrostatic pressure results in the steady filtration of fluid across the capillary bed into the interstitial tissues; this process is increased in the setting of venous hypertension.⁵ In a normal lymphatic system, the interstitial pressure exceeds the luminal pressure, and fluid accumulated in the interstitial tissues is drained by the lymphatics.⁶ Prior studies have shown that interstitial fluid is not reabsorbed on the venous side of the capillary network but instead must rely on clearance by the lymphatics.⁷ When interstitial fluid accumulation exceeds the draining capacity of the lymphatic system edema results. The edema is potentially reversible if the underlying venous disease is treated early.³ However, if this process continues long term as in CVI, there is subsequent irreversible damage to the lymphatics, which results in fibrosis and reflux of the lymphatic system. This further reduces the capacity of the lymphatics to reabsorb the interstitial fluid leading to progressive edema. The combined process of CVI and LED causing extremity edema is often referred to as phlebolymphedema.¹

Although treatment of the underlying venous hypertension may result in improvement in the venous-related symptoms such as claudication and venous ulcers, a significant number of patients with CVI will have persistent swelling which may reflect untreated LED. This study was designed to determine the demographics, outcomes, and healthcare utilization of LED patients with underlying CVI and determine the proportion of CVI-LED patients who underwent LED therapy with manual lymphatic drainage (MLD) or application of pneumatic compression devices (PCD) before and after venous intervention.

Methods

Study design and data source

A retrospective observational design was used to obtain and analyze data from an integrated US healthcare claims repository (IBM MarketScan Commercial Claims and Encounters [CCAE] and Medicare Supplemental and Coordination of Benefits [MDCR] databases). Institutional Review Board approval and informed consent were not required as this study was done through a commercial claims database and no identifiable patient health information was collected. The details of this process have been described in prior publications and the relevant applications will be presented here.⁸

Study population

The study population included patients greater than or equal to 18 years old who were diagnosed with primary or secondary LED between April 1^st 2013 and March 31^st 2019. Patients were diagnosed with LED if they were assigned one diagnosis code for lymphedema in the acute care hospital setting, or at least two diagnosis codes, on two separate occasions, for lymphedema in the ambulatory setting. The earliest incidence of a lymphedema diagnosis code was deemed the “index date.” CVI included patients with a pre-existing or new diagnosis code of edema, skin damage, or venous ulceration.

Exclusion criteria included patients without healthcare coverage during the 12-month period preceding the “index date” or a diagnosis of head or neck cancer before their index dates. Head and neck cancer patients were excluded as presentation differs significantly from extremity lymphedema. Patients were categorized based on their disease etiology.

Study measures

Medical resource utilization MRU was defined by the setting of care, either as an acute care hospitalization or in an ambulatory setting, which was delivered in a physician’s office, hospital outpatient, emergency room, home health, or a skilled nursing facility. This data was obtained from the MarketScan Medicare supplementary database which provides detailed cost and use data for healthcare services performed for inpatients and outpatients. Lymphedema treatment patterns were assessed during the follow-up period, which began on the index date (earliest diagnosis of lymphedema) and ended on the date of health plan disenrollment or the end of the study database, whichever occurred first. Treatments which were specific for lymphedema included manual lymphatic drainage (MLD), simple pneumatic compression device (SPCD), and advanced pneumatic compression device (APCD). Treatments for venous hypertension included ablation of the great and/or small saphenous vein for reflux as well as iliofemoral stent placement for venous obstruction.

Each unique treatment course was identified, beginning with the first, and all qualifying encounters (i.e., with the same Current Procedural Terminology [CPT] or Healthcare Common Procedure Coding System [HCPCS] code) occurring within 30 days of each other were deemed to be part of the same treatment course (codes available in Appendix). Patterns of treatment were characterized in terms of frequency of use, interval from index date to first evidence of treatment, intervals between treatment courses, and duration of treatment courses.

Baseline characteristics

Baseline characteristics of patients in the study population were assessed during the 12-month period prior to their index dates and included demographic profile (age, sex, geographic region of residence, and insurance type); clinical profile (lymphedema-related conditions and comorbidities); and treatment profile (diuretics and anti-inflammatory agents). Lymphedema-related conditions and comorbidities were identified based on ≥1 inpatient encounter or ≥2 outpatient encounters with a corresponding diagnosis code. The codes for the selected conditions, selected drugs, and selected procedures are set forth in the Appendix.

A total of 85,601 patients with LED were identified of whom 8,406 (9.8%) also had a diagnosis of CVI (CVI-LED) (Table 1). The mean age in the CVI-LED group was 66.9 years, and 54.8% were female. Diabetes was present in 38.5% of patients, heart failure in 18.8%, hypertension in 66.3%, obesity in 21.9%, and renal disease in 22.6%. A diagnosis of cellulitis was made during the study period in 35.6% of patients, other infections in 63.9%, DVT in 11.9%, and diuretics were used in 58.2%.

Table 1.

Health characteristics of CVI-LED patients.

Characteristic	CVI-LED (n = 8406)
Age (SD)	66.9 (±14.6)
Sex (% female)	54.8
Comorbidities (%)
Diabetes	38.5
Heart failure	18.8
With beta-blocker therapy	11.8
Without beta-blocker therapy	7.0
Hypertension	66.3
Obesity	21.9
Pulmonary hypertension	4.3
Renal disease	22.6
Use of selected drugs/procedures
Diuretics	58.2
Dressings for venous leg ulcers	8.1
Anti-inflammatory agents	51.1
Lymphoscintigraphy	0.5
LED-associated conditions (%)
Iliac vein disorders (May–Thurner syndrome)	1.4
Cellulitis	35.6
Deep venous thrombosis	11.9
Other infections	63.9

Statistical analysis

Baseline characteristics of patients in the study population were described. Categorical variables were reported as counts and percentages; means and standard deviations were reported for continuous variables. Differences in study measures between CVI-LED patients were evaluated using an independent-samples t test for continuous measures and chi-square/Fisher’s exact test for categorical measures. Significance was accepted at p < .05.

Results

Treatment

Out of the 8,406 patients with CVI-LED, 1051 (13%) underwent venous interventions, the majority of which (911, 87%) had endovenous ablation and 176 (17%) had venous stent placement, with 36 (3%) receiving both treatments (Table 2). Venous ulcer was the indication in 607 (58%) of the patients undergoing intervention, demonstrating that most patients had advanced CVI.

Table 2.

Number of CVI-LED patients receiving LED-specific treatment before and after venous intervention.

Treatment group	Before venous intervention	After venous intervention	p-Value	Time to LED therapy initiation after venous intervention (days)
Ablation or stent placement (1051)	546 (52.0%)	414 (39.4%)	<0.05	273 (±17.3)
Ablation (911)	472 (51.8%)	362 (39.7%)	<0.05	265 (±17.8)
Stent placement (176)	95 (54.0%)	63 (35.8%)	<0.05	347 (± 52)

Number of patients who received LED therapy with MLD or PCD before and after ablation and/or venous stent placement. Standard deviations were included for mean time to LED therapy.

The overall use of lymphedema-specific treatment (MLD or PCD) prior to any venous intervention was reported in 546 patients (51%), but after venous intervention, it was reduced to 414 (39%, p < .05). In the ablation group, 472 patients (52%) received MLD/PCD before undergoing ablation while 362 (40%) received MLD/PCD after ablation (p < .05). The mean time to initiation of lymphedema therapy was 265 days (±17.8) after ablation. In the venous stent group, 95 patients (54%) received therapy with MLD/PCD prior to their interventions, while 63 (36%) received therapy after stent placement (p < .05). The mean time of lymphedema therapy initiation following stent placement was delayed even longer to 347 days (±52).

Expenditures

Medical resource utilization was determined in patients with CVI-LED (Table 3). The median number of acute care hospitalizations was 0.2 visits (range 0–365), and the median number of hospital days was 0.2 (range 0–4,018). The median number of ambulatory encounters in all settings was 42 (range 0–409), including 2 (range 0–252) encounters for home health, and 0 (range 0–208) encounters for skilled nursing facility (SNF) utilization.

Table 3.

Healthcare utilization and expenditures of CVI-LED patients.

	CVI-LED (median [range]) (n = 8406)
Acute-care hospitalizations	0.2 (0–365)
Hospital days	0.2 (0–4018)
Ambulatory encounters
All settings	42 (0–409)
Home health	2 (0–252)
Skilled nursing facility	0 (0–208)
Expenditures for encounters (2019US$)
Acute-care hospitalizations	538 (0–19,184,449)
Ambulatory encounters (all settings)	15,077 (0–1,515,488)
Home health	642 (0–570,755)
Skilled nursing facility	0 (0–230,542)

The median expenditure for acute care hospitalization was $538 (range 0–19,184,449), and the cost for ambulatory treatment in all settings, a composite of Physician office, hospital outpatient, Emergency Room, Physical Therapy/Occupational therapy, skilled nursing facility, and laboratory use, was $15,077 (range 0–1,515,488). The expenditures for home health were $642 (range 0–570,755) and SNF $0 (range 0–230,542).

Discussion

CVI is the second most commonly associated comorbidity or putative cause of LED, with 9.8% of LED patients in this study also having a diagnosis of CVI. CVI is prevalent in the general population, with the literature reporting rates as high as 30%, with advanced CVI having a prevalence of over 600,000 in the United States with an estimated annual cost of nearly 5 billion dollars in 2019.^9–12

In the group of patients who underwent venous intervention in this study, 58% had venous ulcers, indicating the late stage of advanced CVI. There was a high cost associated with the treatment of patients with combined CVI-LED with high rates of medical resource utilization including acute care hospitalizations and expenditures, home health utilization, and SNF utilization, likely in part due to the high rates of comorbidities seen in patients with CVI-LED. Prior studies have demonstrated the significant cost of CVI-LED treatment, with the presence of advanced CVI resulting in a significantly increased cost of care in LED patients.^9,13

Venous hypertension and other hemodynamic changes that occur with CVI result in a spectrum of clinical manifestations including skin changes, varicose veins, claudication, and in advanced stages, venous ulceration.^14,15 Compression therapy is the mainstay in the conservative treatment of CVI. This is typically achieved with compression stockings, which counteracts the venous hypertension and reflux, and improves the associated pain, edema, skin changes, and venous ulcer healing if appropriate compliance is achieved.^16,17 In more advanced CVI and symptoms refractory to conservative management, invasive procedures such as endovenous ablation, venous stent placement, sclerotherapy, and surgery are indicated.^18,19

Due to the impaired lymphatic transport in LED, there is an accumulation of interstitial fluid, increased fat deposition, and connective tissue overgrowth.²⁰ Initially, early lymphatic dysfunction presents as nonspecific tissue swelling which can be difficult to differentiate from swelling due to CVI and can progress to skin thickening, fibrosis, and in rare cases elephantiasis.^21,22 The mainstay of LED treatment includes complete decongestive therapy (CDT) such as MLD and compression therapy with PCDs, with surgical intervention reserved for select cases in which conservative treatment fails or results in suboptimal outcomes.^2,23

While patients with mild symptoms attributable to venous-related symptoms are often treated successfully with conservative compression therapy, there is no consensus on the treatment approach to more advanced cases with a significant LED component which likely requires a combined venous and lymphedema-specific treatment approach.²⁴ In this study, a relatively low proportion of patients (13%) with CVI-LED underwent venous intervention. In the group of patients who underwent venous intervention with either ablation or venous stent placement, over 50% received either MLD or PCD therapy prior to intervention. Nearly 40% of them received therapy after venous intervention with a mean time of LED-specific therapy initiation of 265 days in the ablation group and 347 days in the stent placement group.

Prior reviews have shown that in patients with lower extremity edema, up to 35% will have persistent symptomatic edema after venous stent placement.²⁵ The use of LED-specific treatment in these patients has been shown to be beneficial, with prior studies showing improvement in both patient symptoms and economic burden.^9,26 However, the delay in initiating LED-specific therapy after venous intervention seen in this study suggests that there may be under-recognition of coexisting lymphedema in CVI patients, and further studies are warranted to determine if there is underutilization of LED-specific treatment.

This study has several limitations. The diagnosis of CVI, LED, as well as comorbidities, relies on the proper use of ICD coding, and the correct use of coding must be assumed for claims algorithms. Additionally, the severity of disease cannot be assessed through claims data. Furthermore, the IBM MarketScan Commercial Claims and Encounters database includes only commercially insured patients and may underrepresent Medicare and Medicaid populations. The Medicare Supplemental and Coordination of Benefits database, however, does contain patients with Medicare supplementary insurance provided by employers. The follow-up period was variable between patients, with the index date dependent on the earliest use of an LED-associated ICD code, and follow-up ended on the date of health plan disenrollment or the end of the study database. Finally, the data analysis used in this study ended in 2019 and therefore does not include dedicated venous stents that received FDA approval after that time.

In conclusion, patients with CVI-LED have high rates of comorbidities, infection, and a high economic burden. Prior studies have shown that treating the underlying venous hypertension results in the improvement of certain CVI-related signs and symptoms, though a large proportion of patients will have persistent edema which may reflect untreated LED. This study demonstrated a high percentage of CVI-LED patients requiring LED-specific therapy after venous intervention, with a delay in the initiation of this therapy which could suggest under-recognition of the coexisting LED. Further study is needed in optimizing the treatment of patients with CVI-LED.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MG: none. NL: Medical Advisory Board of Philips and consultant to BARD and Boston Scientific. AG: Chair Advisory Board of Tactile Medical and consultant to Medtronic, BD Bard, and Boston Scientific. TO: Consultant to Tactile Medical. KD: Speaker’s Bureau/Consultant to Cook Medical, Boston Scientific, Becton Dickinson/CR Bard, Medtronic, Penumbra, Tactile Medical, and Philips and consultant to W.L. Gore, Shockwave Medical, Asahi Intecc, Veryan, Cordis, and Surmodics.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

Guarantor

KD.

Contributorship

NL, AG, TO, and KD were involved in the conception of the study. MG wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

ORCID iDs

Nicos Labropoulos

Kush Desai

Appendix

ICD-9-CM and ICD-10-CM codes for LED: 457.0, 457.1, and 757.0; ICD-10: I97.2, I89.0, and Q82.0.

ICD-9-CM and ICD-10-CM codes for CVI: 454.1, 454.8, 454.9, 459.30, 459.32, and 459.39; venous ulcer: 454.0, 454.2, 459.31, and 459.33.

CPT codes for vein ablation: 36473, 36475, 36478, 36482, 37700, 37722, and 37780.

Iliac vein stenting: 37238 and 37239

References

Bunke

Brown

Bergan

. Phlebolymphemeda: usually unrecognized, often poorly treated. Perspect Vasc Surg Endovasc Ther 2009; 21: 65–68. DOI: 10.1177/1531003509337155.

Lee

Andrade

Antignani

, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol 2013; 32: 541–574.

Farrow

. Phlebolymphedema-a common underdiagnosed and undertreated problem in the wound care clinic. J Am Col Certif Wound Spec 2010; 2: 14–23. DOI: 10.1016/j.jcws.2010.04.004.

Santler

Goerge

. Chronic venous insufficiency - a review of pathophysiology, diagnosis, and treatment. J Dtsch Dermatol Ges 2017; 15: 538–556. DOI: 10.1111/ddg.13242.

Michel

Woodcock

Curry

FRE

. Understanding and extending the Starling principle. Acta Anaesthesiol Scand 2020; 64: 1032–1037. DOI: 10.1111/aas.13603.

Mortimer

. The pathophysiology of lymphedema. Cancer 1998; 83: 2798–2802.

Levick

Michel

. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res 2010; 87: 198–210. DOI: 10.1093/cvr/cvq062.

Son

O'Donnell

Jr. Izhakoff

, et al. Lymphedema-associated comorbidities and treatment gap. J Vasc Surg Venous Lymphat Disord 2019; 7: 724–730. DOI: 10.1016/j.jvsv.2019.02.015.

Lerman

Gaebler

Hoy

, et al. Health and economic benefits of advanced pneumatic compression devices in patients with phlebolymphedema. J Vasc Surg 2019; 69: 571–580. DOI: 10.1016/j.jvs.2018.04.028.

10.

Muluk

Hirsch

Taffe

. Pneumatic compression device treatment of lower extremity lymphedema elicits improved limb volume and patient-reported outcomes. Eur J Vasc Endovasc Surg 2013; 46: 480–487. DOI: 10.1016/j.ejvs.2013.07.012.

11.

Kolluri

Lugli

Villalba

, et al. An estimate of the economic burden of venous leg ulcers associated with deep venous disease. Vasc Med 2022; 27: 63–72. DOI: 10.1177/1358863x211028298.

12.

Simka

Majewski

. The social and economic burden of venous leg ulcers: focus on the role of micronized purified flavonoid fraction adjuvant therapy. Am J Clin Dermatol 2003; 4: 573–581. DOI: 10.2165/00128071-200304080-00007.

13.

O'Donnell

Jr. Rosen

, et al. The real cost of treating venous ulcers in a contemporary vascular practice. J Vasc Surg Venous Lymphat Disord 2014; 2: 355–361. DOI: 10.1016/j.jvsv.2014.04.006.

14.

Eberhardt

Raffetto

. Chronic venous insufficiency. Circulation 2014; 130: 333–346. DOI: 10.1161/circulationaha.113.006898.

15.

Partsch

. Varicose veins and chronic venous insufficiency. Vasa 2009; 38: 293–301. DOI: 10.1024/0301-1526.38.4.293.

16.

Dissemond

Assenheimer

Bültemann

, et al. Compression therapy in patients with venous leg ulcers. J Dtsch Dermatol Ges 2016; 14: 1072–1087. DOI: 10.1111/ddg.13091.

17.

Motykie

Caprini

Arcelus

, et al. Evaluation of therapeutic compression stockings in the treatment of chronic venous insufficiency. Dermatol Surg 1999; 25: 116–120. DOI: 10.1046/j.1524-4725.1999.08095.x.

18.

Raju

Darcey

Neglén

. Unexpected major role for venous stenting in deep reflux disease. J Vasc Surg 2010; 51: 401–408. DOI: 10.1016/j.jvs.2009.08.032.

19.

Paravastu

Horne

Dodd

. Endovenous ablation therapy (laser or radiofrequency) or foam sclerotherapy versus conventional surgical repair for short saphenous varicose veins. Cochrane Database Syst Rev 2016; 11: Cd010878. DOI: 10.1002/14651858.CD010878.pub2.

20.

Warren

Brorson

Borud

, et al. Lymphedema: a comprehensive review. Ann Plast Surg 2007; 59: 464–472. DOI: 10.1097/01.sap.0000257149.42922.7e.

21.

Greene

Goss

. Diagnosis and staging of lymphedema. Semin Plast Surg 2018; 32: 12–16. DOI: 10.1055/s-0038-1635117.

22.

Rasmussen

Zhu

Morrow

, et al. Degradation of lymphatic anatomy and function in early venous insufficiency. J Vasc Surg Venous Lymphat Disord 2021; 9: 720–730.e2. DOI: 10.1016/j.jvsv.2020.09.007.

23.

Kayıran

De La Cruz

Tane

, et al. Lymphedema: from diagnosis to treatment. Turk J Surg 2017; 33: 51–57. DOI: 10.5152/turkjsurg.2017.3870.

24.

Scherer

Khilnani

. Evaluation and management of patients with leg swelling: therapeutic options for venous disease and lymphedema. Semin Intervent Radiol 2021; 38: 189–193. DOI: 10.1055/s-0041-1727162.

25.

Raju

. Best management options for chronic iliac vein stenosis and occlusion. J Vasc Surg 2013; 57: 1163–1169. DOI: 10.1016/j.jvs.2012.11.084.

26.

Taradaj

Rosińczuk

Dymarek

, et al. Comparison of efficacy of the intermittent pneumatic compression with a high- and low-pressure application in reducing the lower limbs phlebolymphedema. Therapeut Clin Risk Manag 2015; 11: 1545–1554. DOI: 10.2147/tcrm.S92121.