Perforator vein incompetence in chronic venous disease: A multivariate regression analysis model

Article Outline

• Abstract
• Material and methods
  • Stratification of superficial, deep, and perforator vein incompetence
  • Perforator vein examination
  • Statistical analysis
• Results
• Discussion
• Acknowledgment
• References
• Copyright

Objectives

In the presence of superficial and deep vein insufficiency the effects, if any, of concurrent incompetent perforator veins (IPVs) on clinical status are masked. On the basis of multivariate regression analysis, this study examines the significance of perforator vein incompetence across the clinical classes of CEAP (C-class_CEAP) in relation to the superficial and deep systems, and assesses the role of factors implicated in the presence and number of IPVs in chronic venous disease (CVD).

Methods

The study included 525 limbs in 360 patients, ages 17 to 96 years, referred for investigation of CVD. The protocol entailed history taking, physical examination, and duplex scanning (reflux > 0.5 s), with emphasis on IPVs. Exclusion criteria included peripheral vascular disease, unrelated edema, severe chronic obstructive pulmonary disease, and recent (< 1 year) deep vein thrombosis (DVT).

Results

Limbs were stratified as C₀, 84; C₁, 25; C₂, 231; C₃, 66; C₄, 48; C₅, 23; and C₆, 48. C-class _CEAP was separately regressed with age (P < .001), sex (P < .25), contralateral CVD (P < .2), CVD recurrence (P = .022), previous DVT (P < .001), superficial vein reflux (P < .001); deep vein reflux (P < .001), perforator vein reflux (P < .001), and number of IPVs (P < .001). In an optimized multivariate regression analysis of C class_CEAP with all significant variables combined, age (P < .001), previous DVT (P = .017), superficial vein reflux (P < .001), deep vein reflux (P < .001), and number of IPVs (P = .008) emerged as predictors of CVD severity (CEAP), based on the equation C class_CEAP = −0.2807 + 0.028013 Age + 0.58530 Previous DVT + 0.3450 Superficial vein reflux + 0.17781 Deep Reflux + 0.14537 IPVs (R² = 37.4%; P < .001).Perforator incompetence was predicted by superficial vein reflux (P < .001) and deep vein reflux (P = .044), age (P = .019), CVD recurrence (P = .038), and sex (P = .018), as follows: Perforator incompetence = −0.2532 + 0.006457 Age + 0.41366 Superficial reflux + 0.06766 Deep reflux + 0.2450 CVD recurrence − 0.21310 Sex (R² = 33.3%; P < .001). Number of IPVs per limb was best associated with superficial reflux (P < .001) and deep reflux (P = .023), linked as IPVs = − 0.11789 + 0.41323 Superficial reflux + 0.07646 Deep reflux (R² = 26.1%; P < .001).

Conclusion

Perforator incompetence proved to be a significant factor for determination of CVD severity according to C-class_CEAP, withstanding the conspicuous confounding effects of the superficial and deep venous systems. Perforator incompetence was significantly linked to aging, superficial or deep vein incompetence, recurrence of superficial disease, and sex, whereas the IPV number, regardless of location, depended on the presence of superficial or deep venous reflux.

Appreciation of the effect of chronic venous disease (CVD) on quality of life,¹, ² health services,³ and national budgets⁴, ⁵ over the past decade and the availability of evolved technologies for venous investigation⁶ have ignited scientific research into venous pathophysiology. Yet, despite previous clinical research⁷ and the more recent resurgence of interest in the anatomic and physiologic properties of perforator veins, their clinical relevance in CVD remains as elusive as ever.⁸, ⁹ In addition to the duration of hemodynamic impairment¹⁰, ¹¹, ¹² and the efficacy of calf muscle pump,¹³ instrumental in defining the grade of CVD and its progression are the anatomic distribution¹⁴, ¹⁵, ¹⁶, ¹⁷ and severity¹⁸, ¹⁹ of valvular incompetence. CEAP, as an objective basis of CVD stratification,²⁰ and updated duplex scanning technology that enables high-resolution mapping of valvular incompetence,⁶, ²¹ used together, may provide an investigation acumen able to impart anatomic and physiologic information on the relevance of perforator veins in CVD. The complex interface of causative factors in CVD¹⁶, ²², ²³, ²⁴, ²⁵, ²⁶ supports the methodologic notion that their relative roles could only be roughly determined with linear regression analysis. Yet a study implementing comprehensive multivariate regression analysis of CVD with relation to these factors, including perforator vein incompetence, is unavailable. On the basis of comprehensive multivariate regression analysis the current study examined the clinical significance of perforator vein incompetence across the clinical classes of CEAP (C-classes_CEAP) in relation to the superficial and deep venous systems, and assessed the role of factors implicated in the presence as well as the number of incompetent perforator veins (IPVs) in limbs with CVD.

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Material and methods 

The study included 360 subjects, ages 17 to 96 years, referred consecutively to the vascular laboratory either by the general practitioners of the northwest Thames region in London or the outpatient department of the hospital, representing a population of more than half a million. Demographic data for these patients is given in the Table I. A total of 525 limbs were evaluated.

Table I. Distribution of examined limbs (N = 525) according to C-class_CEAP, CVD with or without recurrence, documented previous DVT, and type and extent of superficial, deep, and perforator reflux, as well as number of incompetent perforator per limb

CVD, Chronic venous disease; DVT, deep venous thrombosis.

Included in the study were subjects with suspected CVD. Exclusion criteria were peripheral vascular disease, either with a deficit in peripheral arterial pulses or resting ankle-brachial index (ABI) less than 1.0; recent (<1 year) deep vein thrombosis (DVT); peripheral edema unrelated to CVD; congestive cardiac failure; symptomatic myocardial ischemia; lymphedema; history of vasculitis or connective tissue disease, and severe chronic obstructive pulmonary disease; venous leg surgery within 10 years; injection therapy in the past 5 years; and history of tibial or femoral fracture.

Examination entailed history taking, physical examination, and determination of ABI. Those subjects who met the study criteria were stratified according to the C-class_CEAP, and underwent lower limb venous duplex scanning. Venous reflux in the lumen of the main axial veins was detected with gated Doppler ultrasound scanning, insonating the entire venous lumen. Patients were examined on a high couch sitting forward, yet with their thighs not touching it, resting the examined foot on a low stool, with the other foot dangling. This position is as close to standing as is feasible, while ensuring venous hemodynamic stability. Reflux immediately after release of firm manual calf compression, generating thorough venous emptying of the calf and thigh veins, was captured with real-time gated Doppler ultrasound scanning, stored in the computer memory of the scanner, and analyzed for flow direction and reflux times. Reflux exceeding 0.5 seconds on 3 consecutive measurements was considered abnormal. Assessment of the venous system included the following veins: common femoral; superficial femoral; profunda femoral; popliteal; peroneal, anterior, and posterior tibial; gastrocnemial; soleal; greater and lesser saphenous and tributaries; perforators; Giacomini; and other superficial unnamed veins.

Suboptimal Doppler waveforms distorted either by motion artifacts or superimposed arterial signals, and those in which segments of the velocity spectrum were not registered were discarded, and an additional reading was obtained. The Doppler settings of duplex sonography were optimized at the preliminary studies, and were consistently maintained thereafter. An optimal angle (60°) of insonation was ensured before flow velocity data were obtained. All duplex studies were conducted under temperature-controlled conditions (22°C ± 1°C) by the same investigator (K.T.D.).

Stratification of superficial, deep, and perforator vein incompetence 

Venous incompetence was stratified as superficial, deep, and perforator. Superficial incompetence was categorized as no reflux (0), non-axial reflux (1), axial reflux above the knee (2), axial reflux below the knee (3), and axial reflux above and below the knee (4).

Deep incompetence was categorized as no reflux (0), non-axial reflux (1), axial reflux above the knee (2), axial reflux below the knee (3), and axial reflux above and below the knee (4).

Perforator incompetence was categorized as no IPVs (0), IPVs above the knee (1), IPVs below the knee (2), IPVs above and below the knee (3), and 5 or more IPVs (4).

Perforator vein examination 

Anatomic and hemodynamic features of perforator veins, identified as distinct interruptions of the deep fascia on transverse real-time B-mode imaging of the calf and thigh, were carefully investigated with color-flow Doppler and gated Doppler ultrasound scanning. Incompetence was defined as outward reflux in the perforator lumen exceeding 0.5 seconds on 3 consecutive measurements immediately after release of standardized, firm manual compression applied distal to the perforator site. Reflux measurements were always performed with gated Doppler ultrasound scanning, insonating the perforator lumen longitudinally at 60° while the vein was being imaged with real-time B-mode. Measurements were conducted in a primed venous system in the position described. The definition of perforator vein incompetence is in keeping with most recent reports.¹⁶, ¹⁷, ²¹, ²⁷, ²⁸, ²⁹, ³⁰

Statistical analysis 

Data analysis was conducted with multivariate linear regression analysis.³¹ Analysis was optimized with sequential, stepwise incorporation of the maximum number of independent variables significantly (P < .05) associated with the dependent parameter, with the purpose of generating best goodness of fit, reflected by R². Inclusion criteria of the independent variables into the multivariate regression analysis were their biologic plausibility and statistical significance (P < .05) when the outcome variable of interest was regressed separately on each potential explanatory independent variable, ignoring all other variables.³¹ The process of forward stepwise multivariate regression analysis of the data enabled determination of optimized models describing the relationship between the dependent and independent parameters of the data. Optimization of multivariate regression was confirmed with application of backward stepwise regression.

The assumptions for multivariate linear regression analysis were tested as follows: (1) The residuals of optimized multivariate regression analyses were examined for normality to establish that the models were an equally good fit throughout the range of values of the dependent variable. Examination of the residuals was performed with the K-S normality test. (2) The normal plot of the residuals in the multivariate regression analyses was evaluated for linearity. (3) A normal cumulative frequency distribution curve of the residuals of the multivariate regression analyses was compared with that of a normal distribution (S-shaped). (4) Appearances of the frequency distribution curves of the residuals of the multivariate regression analyses were matched with those of a normal distribution. Multivariate regression analysis included estimation of the regression constant, regression coefficient, SD, R², t ratio (selectively), and P value for each of the independent variables of the regression. A regression equation was thus provided.³¹ Analysis of variance of the regression analysis was also quoted, offering estimation of the R², sum (of) and mean squares, F value, and significance of the regression model provided.³¹

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Results 

Stratification of the investigated limbs in the C-classes_CEAP; the prevalence of superficial, deep, and perforator vein incompetence, and distribution of IPVs are shown in Table I.

Regression analysis of the C-class_CEAP on each potential explanatory variable, ignoring all other variables, showed that the former was significantly associated with age; CVD recurrence; previous DVT; presence of superficial, deep, and perforator vein incompetence; and number of IPVs (Table II). Forward stepwise multivariate linear regression analysis of these factors revealed that age; previous DVT; superficial, deep, and either perforator reflux (Table III); or number of IPVs (Table IV) were all significant independent determinants of the C-class_CEAP in CVD. Regression equations describing quantitatively the exact relationship of the significant variables with the C-class_CEAP are provided in Table III, Table IV.

Table II. Results of separately regressing the outcome variable of interest, the clinical class of investigated limbs according to C-class_CEAP, on each potential explanatory variable, ignoring all other variables

CVD, Chronic venous disease; DVT, deep venous thrombosis.

Table III. Results of optimized multivariate linear regression analysis of C-class_CEAP on the variables linked to CEAP

Included in regression were all significant factors depicted in Table II, except perforator number. R² of regression is 37.2% (36.6% adjusted). Only factors that maintained statistical significance in multivariate regression are shown. Regression equation of regression was: C-class_CEAP = −0.310 + 0.028462 Age + 0.5930 Previous DVT + 0.34737 Superficial Reflux + 0.17719 Deep Reflux + 0.12997 Perforator reflux.

DVT, Deep venous thrombosis; df, degrees of freedom.

Table IV. Results of optimized multivariate linear regression analysis of C- class_CEAP on the variables linked to CEAP

Included in regression were all significant factors depicted in Table II, except perforator reflux. The R² of regression is 37.4% (36.8% adjusted). Only factors that maintained statistical significance in multivariate regression are shown. Regression equation of regression was: C-class_CEAP = −0.2807 + 0.028013 Age + 0.5853 Previous DVT + 0.34500 Superficial Reflux + 0.17781 Deep Reflux + 0.14537 Perforator number.

DVT, Deep venous thrombosis; df, degrees of freedom.

Regression of perforator vein incompetence on each potential predicting variable in the study, separately, ignoring all other variables, revealed that the former was significantly determined by age, sex, CVD recurrence, superficial reflux, and deep reflux (Table V).At multivariate regression analysis all of these variables also emerged as independent factors linked significantly with perforator vein incompetence (Table VI).

Table V. Results of separately regressing the outcome variable of interest, perforator incompetence, on each potential explanatory variable, ignoring all other variables

Perforator incompetence was classified in 5 groups (0, no perforator reflux; 1, above-knee perforator reflux; 2, below-knee perforator reflux; 3, above-knee and below-knee perforator reflux; 4, five or more incompetent perforator veins).

CVD, Chronic venous disease; DVT, deep venous thrombosis.

Table VI. Optimized multivariate regression analysis of perforator vein incompetence on the variables linked to it

Included in the regression are all significant variables depicted in Table V. The R² of regression is 33.3% (32.7% adjusted). Perforator incompetence as reported in Methods was stratified in 5 groups (0, no perforator reflux; 1, perforator reflux above knee; 2, perforator reflux below knee; 3, perforator reflux above and below knee; 4, five or more incompetent perforator veins). The regression equation of multivariate regression was: Perforator Incompetence = −0.2532 + 0.006457 Age + 0.41366 Superficial reflux + 0.06766 Deep reflux + 0.2450 CVD recurrence − 0.21310 Sex.

CVD, Chronic venous disease; df, degrees of freedom.

Finally, regression of the number of IPVs, per limb, in the study population, separately on each potential variable investigated, ignoring all other variables, showed that the former were significantly related to age, CVD recurrence, superficial reflux, and deep reflux (Table VII). However, at multivariate regression analysis only superficial and deep venous incompetence proved to be significant determinants of the number of IPVs per limb (Table VIII). Tested for the assumptions for multivariate linear regression analysis, the optimized models met the criteria of normality of their residuals (see Material and Methods).

Table VII. Results of separately regressing the outcome variable of interest, the number of incompetent perforator veins, on each potential explanatory variable, ignoring all other variables

CVD, Chronic venous disease; DVT, deep venous thrombosis.

Table VIII. Optimized multivariate regression analysis of the outcome variable of interest, the number of incompetent perforator veins, on the variables linked to it

Included in the regression are all the significant variables depicted in Table VII. The R² of regression is 26.1% (25.8% adjusted). Only the factors that maintained statistical significance in multivariate regression are shown. The regression equation of regression was: Number of incompetent perforating veins = −0.11789 + 0.41323 Superficial reflux + 0.07646 Deep reflux.

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Discussion 

World literature on the hemodynamic and clinical significance of perforator incompetence remains uncertain and divided. Interruption of IPVs in limbs with all-system incompetence that had undergone staged superficial reflux ablation earlier did not reduce ambulatory venous pressure.³² Surgery to treat perforator and superficial incompetence in limbs with concurrent deep reflux did not improve ulceration compared with limbs treated with superficial reflux ablation alone.³³ No hemodynamic benefit was noted in C₂ limbs with perforator and superficial reflux, which had both been ablated compared with limbs that had superficial reflux ablation alone.³⁴ Finally, IPV ablation in post-thrombotic limbs with deep reflux and active ulcers failed to prevent recurrence sustained in 5 years in all 23 limbs.³⁵

Other studies, however, support the clinical value of IPVs. The presence and number of IPVs both increase with CVD severity.¹⁷, ²⁴, ²⁷, ²⁸ In 40 limbs with complicated CVD, post-thrombotic skin changes (15 of 40) and active ulcers (16 of 40) treated with superficial reflux ablation earlier without effect, subfascial disconnection of IPVs (subascial endoscopic perforating vein surgery [SEPS]) resulted in both pain and edema improving in 80% of patients with post-thrombotic limbs and in 74% of those with ulcerated limbs; global venous hemodynamic improvement in 58% of patients; and 56% (9 of 16) of active ulcers that had been active for 0.5 to 21 years before SEPS healing within 14-50 days, reinforcing reports that disconnection of IPVs improves ulcer healing and prevents ulcer recurrence.³⁶ Compared with competent perforator veins, IPVs feature higher peak and mean flow velocity and volume flow,²² longer time to peak reflux velocity, several times greater reflux volume displaced outward, and greater diameter.²², ²⁷, ²⁹, ³⁰, ³⁷ A diameter of 3.5 mm or greaer below the fascia identifies an IPV in 90%,²⁹ yet a third of IPVs have a diameter of 3.9 mm or less.²⁷ Deep reflux enhances peak velocity, volume flow, and displaced volume of IPV reflux.²²

In view of the continuing controversy on the clinical value of IPVs and the multitude of factors that contribute to CVD, the current study used multivariate linear regression analysis to determine the actual association of IPVs with the severity of CVD in 525 limbs encompassing all grades of disease. Using univariate linear regression, we identified that age; recurrence of CVD; superficial, deep, or perforator reflux; number of IPVs; and previous DVT were significantly related to the C-class_CEAP. Multivariate linear regression analysis of the C-class_CEAP of the limbs on these variables defined their actual interrelationship. Age, previous DVT, superficial reflux, deep reflux, and either perforator incompetence or number of IPVs, considered individually, emerged as independent predictors of the C-class_CEAP in a significant proportion (R² = 37.4%; P < .001) of study limbs.

Some of these relationships have been reported in previous studies based on linear correlation analysis alone. The role of superficial reflux in CVD has been noted by several authors.¹⁶, ¹⁷, ²³, ²⁴, ³⁸, ³⁹, ⁴⁰ Also, deep incompetence increases in prevalence with severity of CVD.¹⁶, ¹⁷, ²⁴, ²⁶, ³⁸, ⁴¹, ⁴² The current study, based on a sufficient sample, offers a qualitative and quantitative estimation of the relative contribution of perforator incompetence to the clinical severity of venous disease, withstanding the concurrent effects of superficial and deep incompetence, age, previous DVT, and CVD recurrence.

The outcome of incompetent perforator vein ablation is invariably masked by the overlapping beneficial effect of concomitant superficial vein surgery.⁴³, ⁴⁴, ⁴⁵ The midterm results of the North American SEPS registry included 57 patients who had undergone either SEPS alone (n = 41) or SEPS with avulsion of varicosities (n = 16);⁸ 45 of 57 had active ulcers, and 5 of 57 had healed ulcers. Cumulative ulcer healing was 78% at 1 year and 88% at 2 years, the former being significantly lower than the 96% 1-year healing rate in limbs with active ulcers that had undergone SEPS combined with saphenous reflux ablation. Cumulative ulcer recurrence for C_5-6 limbs was 29% at 1 year and 45% at 2 years, which was higher than recurrence in limbs undergoing SEPS and saphenous stripping (8% at 1 year and 25% at 2 years), yet the difference failed significance (P = .17). This supports the hemodynamic and clinical value of IPVs, because all recruited C₆ limbs had failed conservative care, offered before surgery, with an estimated 75% good to excellent compliance.

The emergence of age as an independent factor linked to the severity of CVD attests to the concept that CVD in its advanced presentation presupposes the action of aggravating impairments over a long period. Scott et al¹⁰ reported that subjects with varicose veins tended to be younger, often with previous phlebitis and a family history of venous disease, in contrast to those with advanced CVD, who were older, often with a long course of deep venous impairment, including DVT and leg injury.

Previous DVT proved to be an independent predictor of C-class_CEAP in the study, highlighting its instrumental role in causing outflow obstruction and valvular incompetence.²¹ Prandoni et al⁴⁶ noted that among patients sustaining DVT post-thrombotic sequelae developed in 23% in 2 years, severe in a third of cases, increasing to 29.1% in 8 years. Follow-up of 73 limbs for 55 ± 26 months from the first DVT showed that only 27% of limbs remained symptom-free, 18% had pain or prominent superficial veins (C₁), 34% had edema, 18% demonstrated hyperpigmentation, and 3% exhibited ulceration.⁴⁷

Factors linked to perforator function in CVD were also jointly examined in a multivariate regression model, to determine their true effect on perforator incompetence and on the number of IPVs. Forward stepwise regression revealed that age, sex, recurrence of CVD, deep reflux, and superficial reflux are predictors of perforator vein incompetence severity in a significant proportion of study limbs (r² = 32%). When the outcome variable in the multivariate model was replaced by the number of IPVs, superficial and deep incompetence emerged as independent predictors (R² = 29.4%).

The occurrence of IPVs in limbs with superficial or deep reflux is well acknowledged. It has been reported¹⁷, ²⁵, ²⁷, ²⁸ that more IPVs occur in limbs with superficial reflux and competent deep veins than in limbs with deep reflux, irrespective of superficial reflux. Large surveys reveal that superficial reflux, particularly in the saphenous trunks, is several times as prevalent as axial deep reflux.²³ Yet IPVs occur proportionally more often in limbs with deep reflux than in limbs without reflux.

The emergence of age as an independent determinant of perforator incompetence in this study parallels its significance in relation to CVD severity. It is suggestive of the length of time taken for CVD to develop¹⁰ and of the relevance of genetic predisposition in deranging venous physiologic features.⁹ It may also point to the susceptibility of aging tissues to protracted venous hypertension. Although never shown in a multivariate regression, the confounding effect of age in the expression of perforator incompetence has been previously noted in a linear regression with the C-class_CEAP.²⁷, ²⁸

Limbs with recurrent varicose veins have been linked previously to a higher likelihood⁴⁸ of perforator incompetence than limbs with primary CVD, reflecting the associated complex reflux patterns, deep vein incompetence, and an inherent susceptibility to CVD.¹⁷, ²², ²⁴, ²⁵ The emergence of recurrent CVD as an independent predictor of perforator incompetence in the current study has not been reported before, to our knowledge. Finally, gender proved to be an additional determinant of perforator incompetence. The study revealed that male subjects demonstrate a significant resilience to perforator incompetence compared with female subjects. Previous studies have recognized the higher likelihood of CVD developing in female subjects. In the Framingham Study primary varicose veins and telangiectases both occurred more often in women at any age, 5.2% developing varicose veins by 2 years of follow-up, in the absence of a history of venous disease, in contrast to 3.9% in men.⁴⁹ Varicose veins were present in 33% of women and 17% of men in southern California, without ethnic differences, in a survey that accounted for equal representation of both genders in 4 ethnic groups.⁵⁰ Yet the link between gender and perforator incompetence has not been reported to date.

In conclusion, perforator incompetence is an independent predictor of the C-class_CEAP, withstanding the conspicuous confounding effects of superficial and deep systems. The severity of perforator incompetence is significantly linked to age, recurrent CVD, superficial reflux, deep vein incompetence, and sex, whereas the number of IPVs, regardless of anatomic location, is predicted independently by superficial and deep incompetence, separately.

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I thank Dr Glena Kulinskaya, PhD, Imperial College, London, so kindly for the insightful comments she offered me in the effort to optimize the regression models.

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