all (n=22 386)
*P<0.05.
†Adjusted for chronic obstructive pulmonary disease, cancer, atrial fibrillation, heart failure, ischaemic heart disease, chronic renal insufficiency.
VV, varicose veins.
MACE risk significantly increased in patients with VV (HR 2.05; 95% CI 1.89 to 2.23; p<0.0001), particularly in relatively younger (age,<65 years; adjusted HR 2.17; 95% CI 1.92 to 2.46; p<0.0001) or male (adjusted HR 2.32; 95% CI 2.06 to 2.62; p<0.0001) patients ( table 3 ). In addition, patients with VV showing cardiovascular risk factors, including hypertension, diabetes, hyperlipidaemia and CAD, were at a higher risk of MACE than were matched controls. In patients with VV, 3-year, 6-year and 9-year MACE-free rates were 91.17%, 84.99% and 79.27%( figure 2A ). These rates dramatically declined further with disease severity ( figure 2B ). In terms of individual cardiovascular outcomes, patients with grade 3 VV were at a greater risk of CHF (adjusted HR 2.05; 95% CI 1.71 to 2.46; p<0.0001), ACS (adjusted HR: 2.04; 95% CI: 1.58 to 2.63; p<0.0001) and ischaemic stroke (adjusted HR 2.06; 95% CI 1.58 to 2.69; p<0.0001) than were controls ( table 4 ). In particular, with the highest VV severity there was an increasing risk of venous thrombotic events, including DVT and PE (grade 3: adjusted HR 38.4; 95% CI 16.4 to 90.1; p<0.0001) ( table 4 ).
(A) Kaplan-Meier estimates of 12-year free from MACE between patients with varicose veins (VV) and the matched control cohort. (B) Kaplan-Meier estimates of 12-year free from MACE between patients with VV categorised by the disease severities and the matched control cohort. MACE, major adverse cardiovascular event.
Crude and adjusted HRs of MACE in patients with VV compared with the matched control cohort during the follow-up period
Cohort all (n=22 386) | Crude HR (95% CI) | P value | Adjusted HR (95% CI)† | P value |
Overall analysis | ||||
VV | 2.08 (1.91 to 2.25) | <0.0001* | 2.05 (1.89 to 2.23) | <0.0001* |
Controls | 1(reference) | 1(reference) | ||
Stratified analysis | ||||
Age (years) | ||||
<65 (years) | ||||
VV | 2.21 (1.95 to 2.5) | <0.0001* | 2.17 (1.92 to 2.46) | <0.0001* |
Controls | 1(reference) | 1(reference) | ||
≧65 (years) | ||||
VV | 1.98 (1.78 to 2.21) | <0.0001* | 1.96 (1.76 to 2.18) | <0.0001* |
Controls | 1(reference) | 1(reference) | ||
Gender | ||||
Male | ||||
VV | 2.35 (2.09 to 2.65) | <0.0001* | 2.32 (2.06 to 2.62) | <0.0001* |
Controls | 1(reference) | 1(reference) | ||
Female | ||||
VV | 1.87 (1.67 to 2.09) | <0.0001* | 1.85 (1.66 to 2.07) | <0.0001* |
Controls | 1(reference) | 1(reference) | ||
Hypertension | ||||
VV | 1.65 (1.42 to 1.92) | <0.0001* | 1.62 (1.39 to 1.89) | <0.0001* |
Controls | 1(reference) | 1(reference) | ||
Diabetes | ||||
VV | 1.4 (1.11 to 1.76) | 0.0042* | 1.37 (1.08 to 1.72) | 0.0081 |
Controls | 1(reference) | 1(reference) | ||
Hyperlipidaemia | ||||
VV | 1.5 (1.03 to 2.17) | 0.0353* | 1.56 (1.07 to 2.29) | 0.0224 |
Controls | 1(reference) | 1(reference) | ||
Coronary artery disease | ||||
VV | 1.93 (1.38 to 2.7) | 0.0001* | 1.99 (1.41 to 2.82) | 0.0001* |
Controls | 1(reference) | 1(reference) |
MACE, major adverse cardiovascular event; VV, varicose veins.
The adjusted HRs of mortality and MACE in patients with VV compared with the matched control cohort during the follow-up period
Grade 1 control | Grade 1 | Grade 2 control | Grade 2 | Grade 3 control | Grade 3 | |
No of mortality, N (%) | 343 (3.62) | 99 (4.01) | 147 (5.79) | 44 (6.59) | 266 (4.65) | 136 (9.01) |
Adjusted HR for mortality (95% CI)† | Referent | 1.08 (0.86 to 1.36) | Referent | 1.13 (0.8 to 1.6) | Referent | 1.83 (1.48 to 2.27)* |
No of CHF, N (%) | 552 (5.82) | 238 (9.65) | 181 (7.12) | 80 (11.98) | 358 (6.26) | 190 (12.59) |
Adjusted HR for CHF (95% CI)† | Referent | 1.68 (1.44 to 1.96)* | Referent | 1.79 (1.37 to 2.34)† | Referent | 2.05 (1.71 to 2.46)* |
No of ACS, N (%) | 291 (3.07) | 125 (5.07) | 72 (2.83) | 24 (3.59) | 174 (3.04) | 95 (6.30) |
Adjusted HR for ACS (95% CI)† | Referent | 1.7 (1.37 to 2.11)* | Referent | 1.25 (0.78 to 1.99) | Referent | 2.04 (1.58 to 2.63)* |
No of ischaemic stroke, N (%) | 236 (2.49) | 99 (4.01) | 90 (3.54) | 31 (4.64) | 162 (2.83) | 89 (5.90) |
Adjusted HR for ischaemic stroke (95% CI)† | Referent | 1.59 (1.25 to 2.01)* | Referent | 1.4 (0.92 to 2.12) | Referent | 2.06 (1.58 to 2.69)* |
No of DVT+PE, N (%) | 14 (0.15) | 56 (2.27) | 7 (0.28) | 13 (1.95) | 6 (0.10) | 63 (4.17) |
Adjusted HR for DVT+PE (95% CI)† | Referent | 14.9 (8.26 to 26.86)* | Referent | 6.27 (2.46 to 15.96)* | Referent | 38.42 (16.38 to 90.13)* |
ACS, acute coronary syndrome; CHF, congestive heart failure; DVT, deep vein thrombosis; MACE, major adverse cardiovascular event; PE, pulmonary embolism; VV, varicose veins.
During 2010–2015, a total of 2202 outpatients and 347 inpatients were reported to have VV in Chi-Mei Medical Center. Among the outpatients, 1188 were coded as uncomplicated VV (ICD-9-CM code 454.9), 775 were coded as VV with inflammation (ICD-9-CM code 454.1), 152 were coded as VV with ulcers (ICD-9-CM code 454.0) and 87 were coded as VV with ulcer and inflammation (ICD-9-CM code 454.2) ( online supplementary table 3 ). Notably, none were coded incorrectly. Compared with CEAP stage, as determined based on chart reviews, only a few inpatients were incorrectly or unclearly diagnosed using ICD-9-CM-derived VV codes ( online supplementary table 4 ). For example, among patients with higher VV grades (CEAP stage 5–6), the positive and negative predictive values with ICD-9-CM-derived codes were 93% and 98.4%, respectively. Specifically, the sensitivity and specificity of ICD-9-CM-derived grading were up to 95.2% and 97.6%, respectively. The calculated kappa score between CEAP stages and grading severity is 0.92 (95% CI 0.88 to 0.96).
VV and controls with pregnancy history were identified and examination the influence in sensitivity analysis ( online supplementary table 5 ). After additionally adjustment for history of pregnancy, the results remain showing great impacts on mortality and MACE (adjusted HR for death (1.37 (95% CI 1.19 to 1.57), p<0.0001; adjusted HR for MACE 2.01 (95% CI 1.89 to 2.23), p<0.0001).
After excluding 472 subjects with Myocardial infarction, stroke, coronary angioplasty or CABG, remaining VV and corresponding controls were included for sensitivity analysis. Comparing with corresponding matched controls, those conservatively treated VV patients were found 1.36 times risks of mortality (adjusted HR 1.36 (95% CI 1.18 to 1.57), p<0.0001) and 1.95 times risks of MACE (adjusted HR 1.95 (95% CI 1.80 to 2.12), p<0.0001).
The primary findings of this study were that (1) patients with VV were at increasing risks of mortality and cardiovascular events, especially those with VV at grade 3 compared with matched controls; (2) having VV had a significant impact on the survival of male patients. To the best of our knowledge, this nationwide population-based study is the first to comprehensively describe the association of VV with patients’ cardiovascular outcomes.
Although VV are common, their potential threat to health has not been well investigated previously. 1 2 Valve dysfunction-mediated activation of leukocytes, release of enzymes and remodelling of the vascular wall lead to venous valve destruction and incompetence. 11 VV may cause inflammation, oedema, ulcers, 11 endothelial dysfunction 12 and subsequent DVT. 5 In addition, overexpression of inducible nitric oxide synthase and transforming growth factor-β1 has been documented in patients with VV. 13 In this study, the risk of all-cause mortality and MACE was higher in patients with VV than it was in matched controls, indicating that VV-induced systemic inflammation may be associated with cardiovascular events regardless of the development of venous thromboembolic events. Notably, the lower survival rates were observed in patients with highest VV severity but not in those with grade 1–2. This also reflects that the chronic inflammation induced by a higher grade of VV may be associated with increasing mortality and MACEs. However, only a few studies have compared development of VV with arterial disease and reported inconsistent findings. 2 14 A previous study in Finland has reported a twofold higher incidence of new arterial disease in individuals with VV than in those without it, although the incidence of new hypertension was similar. 14 15 Thus, VV and arterial disease may have a common aetiology, but VV were not related to hypertension. Furthermore, Chang et al have reported the association of VV with the incidence of venous thromboembolism and PAD. 16 Reportedly, myocardial infarction and heart failure increase the risk of thromboembolism. 17 In contrast, patients with thromboembolic events were at a higher risk of subsequent myocardial infarction and stroke. 18 However, whether this association is causal or represents common risk factors warrants further research. Notably, compared with controls, patients with VV were at a higher risk of mortality independent of age and sex. Specifically, the significant impact of VV was observed in male patients. In previous research, older age and female sex were found to be the most relevant risk factors for VV. 1 VV incidence increases with increasing age. However, Heit et al have reported that younger patients with VV were at a significantly increased risk of subsequent DVT, whereas the risk was attenuated with increasing age. 7 Similarly, Lohr et al also reported that although female presented with a higher prevalence of lower grade VV (CEAP 2–3) compared with male (50.5% vs 30.1%), there were more higher grade VVs with trophic skin changes (CEAP 4–6) found in male than in female (5.4% vs 2.8%). 19 Also, DVT was more common in males compared with females (11.3% vs 7.8%). 19 Earlier onset of VV in the younger population implies a higher risk of concomitant arterial diseases or systemic inflammations. As described previously, female sex, pregnancy, and predominately being in the sitting posture are risk factors for VV. 20 However, despite the valid correlation between use of oestrogen supplements and DVT, whether sex hormones contribute to the development of VV remains unclear.
There were several strengths of this study. First, we included an unselected, large, nationwide cohort of patients with VV. By including the data of 4644 patients over a 12-year period, this study provided adequate statistical power for the analysis of long-term outcomes for VV. Second, we compared the VV cohort with a matched, VV-free cohort, which helped distinguish the characteristics of the VV population in terms of survival and outcomes. Third, among patients with VV, the effects of sex on mortality and MACE were emphasised because VV may have been ignored in these specific populations. Forth, we included patients presenting with VV of various severity grades, which allowed for a comprehensive investigation of overall effects of severity. Finally, a recently published article evaluated and supported the accuracy of several major outcomes, including MI, hypertension, diabetes, stroke, CHF and VV, in NHIRD. 21
However, this study had several limitations. According to previous meta-analysis and research, smoking habits, quality of life, lack of movement, pregnancy history, overweight and glycated haemoglobin levels are considered VV risk factors, with some of these being related to increased mortality risk. Although NHIRD provides a complete clinical medical history over decades for 1 million people, currently the NHIRD lacks information regarding people’s lifestyle and clinical laboratory test results. Therefore, the selected confounders in this study were limited to age, sex and four chronic cardiovascular risk factors. The small corresponding area under the receiver operating characteristic curve indicated that the relevant confounders were not appropriately identified. To explore the effects of VV on mortality and MACE with minimum confounding bias, a future study including more comprehensive VV-related risk factors is imperative. Second, the miscoding of VV severity may have led to the exclusion of cases. This might explain why 47% of the included patients are with advanced venous disease (grade 2 or 3), different from the general distribution of disease severity. Nevertheless, to overcome the inherent limitations, we verified the accuracy of VV diagnosis using chart review by a specialist. Overall, both the validation methods indicated a satisfactory accuracy of VV coding in the NHI database. Third, owing to difficulties in completing CEAP staging according to ICD-9, we established our own grading system. However, even though this novel ICD-9-CM-derived grading system clearly differentiated patients with various severities, it remained different from the generally applied CEAP staging system and disease progression could hardly be represented. Similarly, to validate the reliability of the ICD-9-CM-derived grading system, we reviewed medical records of inpatients with VV and observed satisfactory sensitivity and specificity. Forth, while ligation and stripping surgeries may affect the outcomes, through excluding patients receiving surgical treatment for VV we performed sensitivity test. It also revealed significant increases of risks of mortality and MACE in patients with VV compared with risks in the matched controls. Likewise, after excluding the potential influences of PAD, we also found great impacts of mortality and MACE in the population with VV. Finally, increased mortality with higher ICD-9-CM-derived grades indicated that our grading system specifically reflected the severity of VV but the cause of mortality was not available in this database.
VVs are a common condition typically believed to be benign; however, our results suggest that they warrant close attention. Compared with matched controls, patients with VV were at increasing risks of mortality and cardiovascular events, especially those with VV at grade 3. Therefore, these findings should alert clinicians regarding the importance of detecting VV at an early stage.
N-CW and Z-CC contributed equally.
Contributors: All authors contributed to the revision of the manuscript and approved the final version. All agreed to be accountable. N-CW contributed to concept and design, critical revision. Z-CC contributed to data collection and critical revision. I-JF contributed to critical revision, data collection, statistical analysis and interpretation. C-HH contributed to critical revision, data collection, statistical analysis and interpretation. C-YC contributed to data collection and critical revision. J-JW contributed to data collection and critical revision. W-TC contributed to concept and design, data collection, interpretation, manuscript writing and critical revision.
Funding: We received the research grant supported by Chi-Mei Medical Center
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication: Not required.
Ethics approval: The present study was ethically approved by the Institutional Review Board of Chi-Mei Hospital (CV code: 10406-E01). All procedures followed the principles outlined in the Declaration of Helsinki.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data are available in a public, open access repository. All the data are available in National Health Insurance Research Database (NHIRD) in Taiwan.
Background: Varicose veins of the lower limb are the most common peripheral vascular disease. A clinical study and surgical management of varicose vein was conducted to study the age, sex and occupational distribution of varicose veins of lower limb. Evaluations of clinical features and surgical methods of treatments that were in practice in the management of varicose veins in terms of recurrence and symptoms improvement were alsostudied. Methods: A prospective study was carried out between July 2013 to June 2015. During this period 50 cases of varicose veins of lower limbs were admitted to our hospital and were studied in detail. After thorough clinical examination and relevant investigation they are all subjected to surgical management. Results: Out of 50 cases studied, 35 (50%) had long saphenous vein involvement, 6 (12%) had short saphenous vein involvement and in 5 (10%) cases both short and long saphenous system were involved. In addition to long saphenous vein involvement, incompetent perforators were present in 4 (8%) cases. Among them prominent veins and pain were the main complaints in 36 (72%) patients. Itching and pigmentation were present in 7(14%) patients. Ankle edema was present in 4(8%) patients. Pain and ulceration of lower leg were present in 3(6%) patients. After clinical assessment appropriate surgical procedures were followed for each of patients. Conclusions: This study reveals that the disease is more prevalent during the active adult life in their 3rd and 4th decades and males were more affected. Definite relationship exists between the occupation and the incidence of varicose veins. The patients were in the occupation which required standing for long time had the higher chances of varicose vein. Severity of the symptoms is not proportional to the duration of varicose veins. The involvement of long saphenous vein is more common than the short saphenous vein. Since our study shows very low percentage of recurrence and symptoms related to varicose vein the surgical line of treatment is an ideal treatment for varicose vein. If cases are selected properly with good operative technique the complications are negligible.
[ K. VANI and D. REDDY PRASAD (2015); CLINICAL STUDY AND MANAGEMENT OF LOWER LIMB VARICOSE VEINS Int. J. of Adv. Res. 3 (Oct). 1778-1784] (ISSN 2320-5407). www.journalijar.com
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