Association between cardiac conditions with venous leg ulcers in patients with chronic venous insufficiency

Abstract

Introduction

Venous leg ulcers (VLUs) are the final stage of chronic venous insufficiency. This study aims to characterize the association between cardiovascular diseases and VLU.

Methods

A multicentric case-control study analyzed 17,788 patients between 2015 and 2020. Cases were matched (1:2) by age and sex, and odds ratios (OR) were analyzed with conditional logistic regressions adjusted by risk factors.

Results

The prevalence of VLU was 15.2%. 2390 cases were analyzed. Diseases found to be associated with VLU were atrial fibrillation (OR, 1.21; 95% CI: 1.03–1.42), pulmonary hypertension (OR, 1.45; 95% CI: 1.06–2.00), right heart failure (OR, 1.27; 95% CI: 1.13–1.43), peripheral artery disease (OR, 2.21; 95% CI: 1.90–2.56), and history of pulmonary embolism (OR, 1.45; 95% CI: 1.06–2.00).

Conclusions

Certain cardiovascular conditions showed an association with VLU. Further studies are warranted to evaluate the effect that treating concomitant cardiovascular diseases might exert on the natural history of venous leg ulcers.

Keywords

venous leg insufficiency venous leg ulcers heart failure atrial fibrillation pulmonary hypertension right heart failure

Introduction

Venous leg ulcers (VLUs) are a severe complication of chronic venous leg insufficiency (CVI) that affects 1–3% of the United States.^1–3 VLU is a late stage of CVI (Clinical Etiological Anatomical Pathophysiology [CEAP] classifications C5–C6) that increases in prevalence among the elderly. Around 4% of adults over 65 with CVI have venous ulcers.^4–8 VLU represents a physical and financial burden on patients, as recurrence rates are estimated to be between 50% and 70% within 6 months, increasing the treatment costs while decreasing the quality of life.^9–13 The healthcare system is also weighed down by the cost of VLU, as expenses are estimated to be near $15 billion annually.^14,15

Currently, the mainstay of treatment for VLU focuses on managing the local ulcer with conservative compression therapy or venoactive drugs.^10,11 However, these methods fail to address the underlying systemic pathophysiology of venous hypertension and focus on the localized healing process in the leg.^6,16 Although the right heart is directly connected to the venous system and the cardiopulmonary system is responsible for tissue oxygenation; there is currently limited research on the association with venous diseases. Some studies have found heart failure as a risk factor for VLU, but these studies did not investigate diseases such as atrial fibrillation or pulmonary hypertension.^7,10,17–21 These conditions may contribute to the pathophysiology of venous hypertension, hypoxia, and subsequent ulceration.

A retrospective chart review was performed on 26 patients with CEAP six venous disease as a pilot study. Common comorbidities identified were pulmonary hypertension (73.1%), right heart failure (46.2%), chronic obstructive pulmonary disease (COPD - 34.6%), and atrial fibrillation (34.6%). After the initial results, we expanded the study to examine these associations on a larger scale. This study aimed to demonstrate the association between concomitant impaired cardiovascular and pulmonary function in patients with CVI and VLU occurrence. We hypothesize that diseases such as atrial fibrillation, right heart failure (RHF), and pulmonary hypertension will be associated with VLU among patients with chronic venous insufficiency. Identification of these associations will expand the literature on conditions that may be screened for and perhaps treated concomitantly in patients with VLU in the future to prevent ulceration or improve healing times.

Methods

Pilot

We performed a retrospective chart review from a single vascular center with patients seen between January 2017 and March 2020. All patients with active venous ulcers (C6 and CVI) were included. Patients were routinely asked about their past medical history. Data collection had baseline demographics, comorbid conditions, vital signs, body mass index, electrocardiogram, and echocardiogram.

Design

A case–control study was designed to evaluate the association of cardiac conditions, especially atrial fibrillation, with venous leg ulcers in patients with chronic venous insufficiency by conducting a retrospective chart review, including all the patients with CVI (C: 1 to 6, E: primary or secondary, A: superficial or perforating, P: reflux or obstruction) evaluated between January 2015 and December 2020 at a Hospital System (more than eight hospitals). Variables included baseline demographics, comorbidities (past medical history, health problem, medical diagnosis) with a cardiovascular or chronic inflammation component, such as atrial fibrillation, right heart failure, arterial and pulmonary hypertension, type 2 diabetes mellitus, thyroid diseases, cancer, rheumatoid arthritis, chronic kidney disease, dyslipidemia, obstructive sleep apnea, smoking, multiple sclerosis, lymphedema, pulmonary embolisms, deep vein thrombosis, alcohol consumption, cirrhosis, portal hypertension, chronic obstructive pulmonary disease, and peripheral arterial disease, vital signs, body mass index, complete blood count, comprehensive metabolic panel, and hemoglobin A1C. To minimize Berkson’s bias, cases, and controls were selected from the electronic medical record associated with any visit to one of these hospitals, including ambulatory centers and main hospitals. The disease was also unrelated to hospital admission. Institutional Review Board approved the study protocol.

Case and Control

Inclusion criteria: Cases included ≥29-year-old patients with CVI and active or healed VLU—C5 or C6. Controls were ≥29-year-old, with CVI—C1 to C4.

Exclusion criteria: Patients without electronic medical record data and older than 90 years old.

Cases were exactly matched by sex and age with two controls (1:2), then a second analysis was done adjusted by type 2 diabetes, obesity, peripheral artery disease, lymphedema, and deep vein thrombosis. Cardiac conditions were analyzed and compared with well-known risk factors of VLU.^1–10

Statistical analysis

Continuous parameters are described using mean ± standard deviation or median (interquartile range). Categorical parameters are described overall using values and percentages. Also, multiple logistic regressions were done to calculate odds ratios and confirm any correlation type. Continuous variables were compared using a t test, and χ² was used to compare results between categorical variables. Finally, odds ratios were calculated. McNemar’s test was done for univariate contingency tables to determine any differences in dichotomous dependent variables between the matched pairs and conditional logistic regression for adjusted analyses with Cox model; a p value <.05 was considered statistically significant. IBM SPSS Statistics, version 23 (SPSS Inc., Chicago, Ill., USA) was used to conduct all statistical analyses.

Results

Pilot

Twenty-six patients were identified with a median age of 68 (58–77) years old. Fourteen (53%) were male, and 23 (89%) patients had obesity with a median BMI of 38 (31–46) kg/m². The most common comorbidities were hypertension (80.8%), pulmonary hypertension (73.1%), type 2 diabetes (61.5%), right-sided heart failure (46.2%), COPD (34.6%), and atrial fibrillation (34.6%). Concomitant with active VLUs, 30.8% of patients had lymphedema, 38.5% had a history of tobacco consumption, 30.8% had peripheral artery disease, 35.5% had hyperlipidemia, 30.8% had chronic kidney disease, 26.9% had hypothyroidism, and 23.1% had obstructive sleep apnea.

Case-Control Study

Before the matching, a total of 17,788 patients met the inclusion criteria; 2704 were cases (VLU), and 15,084 were controls (CVI). The average age was 68.9 ± 14 years in the cases and 65.2 ± 15 in the controls group (p < .001). The gender distribution was different between the two groups; cases had more males (52%) and controls with more females (61%, p < .001). Age and male sex had a positive association (p < .001); the ORs were 1.02 (1.02–1.02 (95% CI)) and 1.70 (1.58–1.83), respectively.

The following are the vital signs collected (resting) during the visit associated with the vascular diagnosis (VLU or CVI). The heart rate in the cases was 78 ± 18 bpm and 83 ± 20 bpm (p < .001) in the controls. The systolic and diastolic pressure did not differ between both groups (136/76 mmHg) nor the respiratory rate (18 bpm). The average BMI was 36 ± 17 kg/m² in the cases and 32 ± 9.4 kg/m² (p < .001) in the controls. VLU had a prevalence of 15% in our cohort of patients with CVI.

Matched

In total, 2390 cases were exactly matched with 4780 controls. Table 1 summarizes the characteristics of cases and controls after matching them by age and sex with a statistically significant association. The strongest positive association exists between lymphedema and rheumatoid arthritis. Also, a negative association was seen with the use of statins in patients with hyperlipidemia. Therefore, we did a second analysis with the most critical risk factors of VLU.^3,16,18 The results of the conditional logistic regression adjusted by type 2 diabetes, obesity, peripheral artery disease, lymphedema, and deep vein thrombosis are presented in Table 2 (Figure 1). Patients with VLU—C5/C6 versus those with VLI—C1/C4 have a 21%, 47%, and 27% increased odds of having atrial fibrillation, pulmonary hypertension, and RHF, respectively.

Table 1.

Characteristics of cases and controls matched by age and sex.

Variables	Cases (n = 2390)	Controls (n = 4780)	p value	Odds ratio (95% CI)
Atrial fibrillation	406 (17%)	614 (13%)	<0.001	1.38 (1.21–1.59)
Pulmonary hypertension	127 (5.3%)	148 (3.1%)	<0.001	1.76 (1.38–2.24)
Right heart failure	634 (27%)	809 (17%)	<0.001	1.77 (1.58–1.99)
Type 2 diabetes mellitus	1072 (45%)	1359 (28%)	<0.001	2.05 (1.85–2.27)
Obesity (BMI >30 Kg/m²)	847 (35%)	1047 (12%)	<0.001	1.96 (1.76–2.18)
Hypothyroidism	272 (11%)	459 (9.6%)	0.020	1.21 (1.03–1.42)
Controlled hyperlipidemia	840 (35%)	1737 (36%)	0.005	0.89 (0.81–0.99)
Rheumatoid arthritis	83 (3.5%)	66 (1.4%)	<0.001	2.57 (1.85–3.56)
Chronic kidney failure	577 (24%)	656 (14%)	<0.001	2.00 (1.77–2.27)
Arterial hypertension	983 (41%)	1224 (26%)	<0.001	2.03 (1.83–2.25)
Active smoking	203 (9.5%)	219 (4.6%)	<0.001	1.93 (1.59–2.36)
Lymphedema	634 (27%)	288 (6.0%)	<0.001	5.63 (4.85–6.54)
Pulmonary embolism	100 (4.1%)	101 (2.1%)	<0.001	2.02 (1.53–2.68)
Deep venous thrombosis	142 (5.9%)	163 (3.4%)	<0.001	1.79 (1.42–2.25)
Cirrhosis	86 (3.6%)	101 (2.1%)	<0.001	1.73 (1.29–2.32)
COPD	294 (12%)	385 (8.1%)	<0.001	1.60 (1.36–1.88)
Peripheral artery disease	539 (23%)	509 (11%)	<0.001	2.44 (2.14–2.79)
Osteoarthritis	351 (15%)	452 (9.5%)	<0.001	1.65 (1.42–1.91)
Gout	116 (4.9%)	165 (3.5%)	<0.001	1.43 (1.12–1.82)
Anemia	505 (21%)	468 (10%)	<0.001	2.47 (2.15–2.83)

The data are presented as the number of patients (%); Odds ratio, odds of the event in cases divided by the odds of the event in the control group; CI, confidence interval. COPD, chronic obstructive pulmonary disease; McNemar’s test was used for paired dichotomous variables and univariate contingency tables.

Table 2.

Multivariate analysis of factors associated with venous leg ulcers in patients with chronic venous insufficiency.

Variables	OR (95% CI)^a	p value
Atrial fibrillation	1.21 (1.03–1.42)	0.018
Atrial hypertension	1.94 (1.72–2.19)	<0.001
Pulmonary hypertension	1.42 (1.07–1.87)	0.014
Pulmonary embolism	1.45 (1.06–2.00)	0.022
Chronic obstructive pulmonary disease	1.18 (1.01–1.38)	0.033
Right heart failure	1.27 (1.13–1.43)	<0.001

CEAP 6 = 100%, PAD = 2.21 (1.90–2.56), p < 0.001.

^aOR, adjusted odds ratio; CI, confidence interval; a conditional logistic regression was used to adjust odds ratios by type 2 diabetes mellitus, obesity, peripheral artery disease, lymphedema, and deep vein thrombosis.

Figure 1.

Illustration of co-morbidities associated with venous leg ulcers in patients with chronic venous insufficiency.

Discussion

This study explored the risk factors associated with VLU in patients with CVI, mainly the effects of concomitant cardiovascular and pulmonary diseases. The venous system, principally in the legs, is directly related to the right heart, and several known risk factors for atrial fibrillation are also found to contribute to VLU development. Although it is unclear which pathology comes first, we found a statistical association between atrial fibrillation and VLU. Moreover, right heart failure, pulmonary hypertension, COPD, arterial hypertension, and pulmonary embolism are also associated with VLU.

We used a case–control study as the gold standard design to identify risk factors. We found that type 2 diabetes, obesity (BMI >30 Kg/m2), hypothyroidism, rheumatoid arthritis, chronic kidney failure, smoking, lymphedema, deep venous thrombosis, cirrhosis, peripheral artery disease, osteoarthritis, gout, and anemia are independent risk factors of VLU. In addition, the demographic characteristics of our findings are consistent with the literature; most cases of CVI are women. However, the majority of patients with VLU are men.^1,18,22

Previous data reported by Augey et al.¹⁸ showed a strong association between stasis venous ulcer and right heart failure (RHF) (OR = 4, 7; (2.1–10.4)); a significant association between RHF and bilateral localization of VLU ulcers was also found. Likewise, it is essential to highlight that RHF has been associated with chronic venous disease and primary CVI.¹⁹ After adjustment, we found similar results, with a significant positive association between atrial fibrillation (OR: 1.21), RHF (OR: 1.27), pulmonary hypertension (OR: 1.42), and COPD (OR: 1.18) with VLU. Since these comorbidities increase the risk of ulcers, closer surveillance plans should be designed for patients with CVI and the above-mentioned comorbidities. They might include a more aggressive sequence of follow-up appointments with the vascular surgeon and cardiologist, correction of superficial reflux, compression stocking, maintaining an optimal BMI, and avoiding skin trauma in the affected lower limb to prevent ulceration. Adjuvant pharmacological venoactive drug therapy might be considered as well.

Cardiopathies like atrial fibrillation and RHF share some well-known risk factors, including age > 65 years, male sex, hypertension, type 2 diabetes, obesity, and smoking; even atrial fibrillation is a risk factor itself for developing RHF and vice versa.^23,24 Interestingly, these risk factors are exhibited by most C5 and C6 patients. This finding provides additional support to the statistical association between atrial fibrillation and RHF with VLU and opens the door to a possible common etiologic pathway between these diseases. Hence, clinical providers should be aware of patients with CVI and atrial fibrillation or RHF, especially men, who should be identified as a higher risk group for developing VLU.

On the other hand, we demonstrated a negative association between controlled hyperlipidemia and VLU, which could explain an indirect protective effect from statins in these patients. Although the type or doses of statin regimen were not collected, there was an 11% statistically significant reduction of VLU risk in patients with controlled hyperlipidemia.

Furthermore, clinical providers should be encouraged to identify ulcers and delayed wound healing risk factors, especially in those patients with chronic inflammation or diseases such as type 2 diabetes, arterial hypertension, and obesity.²⁵ Moreover, it is essential to highlight the link between the cardiovascular and pulmonary systems and the venous system, especially the association between right-sided heart dysfunction, COPD, or pulmonary hypertension with venous hypertension and ulcers, as demonstrated in previous studies.^17–19,21 Accordingly, VLU should be ideally approached by a multidisciplinary team to address all the components of ulcers, wound healing, recurrence, and recurrence prevention. Hopefully, emerging technologies will impact the management of VLU, including standardized wound healing indexes,²⁶ genomic studies,²⁷ imaging, labs, and clinical history.^28,29

Finally, our results suggest that patients with CVI and VLU should receive a multidisciplinary approach to screening for pulmonary and cardiac diseases. Echocardiographic and electrocardiographic screening would be ideal for determining concomitant atrial fibrillation or RHF. However, this is a case–control study, and our findings only provide information about the association. Another limitation is the lack of CEAP classification and severity of co-morbidities for each patient, so the strength of association with the incidence of VLU could not be calculated. Accordingly, further prospective cohort studies are warranted to establish causality and progression timing between RHF, atrial fibrillation, and VLU; and to determine the economic benefits of cardiologic screening for patients with VLU. Finally, those with VLU—C5/C6 disease may be used to identify patients with higher odds of having cardiac conditions. This may aid the diagnosis or serve as a marker for how well the underlying disease is controlled. We recommend cardiopulmonary screening during the initial examination of patients with VLU.

Conclusions

Patients with VLU—C5/C6 disease have increased odds of having cardiovascular and pulmonary diseases, such as atrial fibrillation, right heart failure, pulmonary hypertension, pulmonary embolism, arterial hypertension, chronic obstructive pulmonary disease, obstructive sleep apnea, chronic kidney disease, peripheral arterial disease, type 2 diabetes mellitus, and lymphedema. Individuals with VLU and common risk factors for atrial fibrillation or right heart failure should undergo routine cardiologic assessments. Finally, further prospective studies are warranted to evaluate causality and to better understand and quantify the impact of treating cardiac conditions in the progression of chronic venous disease and ulcer prevention.

Footnotes

Author note

This study was presented at the Annual Meeting of the European Society of Vascular Surgery, ESVS 2021 fast-track. The pilot study was presented at the Annual Meeting of the American Venous Forum, AVF 2021 virtual.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

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

ORCID iDs

Alejandro Pizano

Sebastian Cifuentes

Valentin Figueroa

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