Varicose veins associated with higher risk of deep vein thromboses, pulmonary embolisms, and peripheral arterial disease

1. In this case-control study, patients with varicose veins were at higher risk of deep vein thromboses (DVTs), pulmonary embolisms (PEs), and peripheral arterial disease (PAD).

2. Varicose veins inferred a greater increase in risk in younger patients for DVT and PAD, and men with varicose veins were at higher risk of PAD than women.

Evidence Rating Level: 2 (Good)

Study Rundown: Varicose veins is a highly prevalent disease in adults and is associated with increased inflammation in the vascular system. However, while some smaller cohort studies have tried to estimate the risk of other adverse vascular events and disease, a large cohort study has yet to be completed. In this Taiwanese, case-control cohort study, patients with varicose veins had a higher rate of Deep Vein Thromboses (DVTs), Pulmonary Embolisms (PEs), and Peripheral Arterial Disease (PAD). These results remained significant even when controlling for a number of other co-morbidities and risk factors. For DVT and PAD, varicose veins inferred a greater increase in risk in younger patients, and men with varicose veins were at higher risk of PAD than women. As a negative control, hemangioma was not associated with increased risk of DVT or PE but was associated with a slight decreased risk for PAD. Analysis estimating the potential effects of unmeasured confounders did support a possibility of unknown confounders influencing the association between varicose veins and PE and PAD, but the association with DVT remained robust.

The rigor and large sample size of this study greatly strengthen the conclusions of the study, though some limitations remain. The most important limitation concerns the retrospective nature of the study, and future prospective cohort studies with careful documentation of confounders, especially smoking, would be especially helpful in supporting this study’s conclusions.

Click to read the study, published in JAMA

Relevant Reading: Persons With Varicose Veins Have a High Subsequent Incidence of Arterial Disease: A Population-Based Study in Tampere, Finland

In-Depth [case-control]: A total of 212 984 patients were analyzed from the National Health Insurance (NHI) program in Taiwan from 2001 to 2013, with a 4:1 control-to-varicose-vein, age- and sex-matched cohort. Patients were excluded if they were younger than 20 years of age or if they had a diagnosis of DVT, PE, or PAD prior to their varicose vein diagnosis or index date for age-matched controls. Control for the following confounding factors were included in the analysis: sex, age, index year, number of outpatient visits during the year before index date, and comorbidities including hypertension, diabetes, chronic obstructive pulmonary disease, hyperlipidemia, malignancy, heart failure, ischemic heart disease, stroke, and chronic renal insufficiency.

Validation of the varicose vein diagnosis revealed a positive predictive value (PPV) of 98% (CI₉₅ 0.95 to 0.99%) with a worse case PPV of 82% (CI₉₅ 0.77 to 0.87%). Varicose veins increased the risk of DVT (HR 5.30; CI₉₅ 5.05 to 5.56), PE (HR 1.73; CI₉₅ 1.54 to 1.94), and PAD (HR 1.72; CI₉₅ 1.68 to 1.77). For DVT and PAD, varicose veins inferred a greater increase in risk in younger patients, and men with varicose veins were at higher risk of PAD than women (p < 0.05). As a negative control, hemangioma was not associated with DVT (HR 1.09; CI, 0.99 to 1.20) or PE (HR 1.02; CI₉₅ 0.81 to 1.28) but was associated with a decreased risk for PAD (HR CI₉₅ 0.78 to 0.86). Analysis for two falsification endpoints, hyperlipidemia and lung cancer, were weakly associated with varicose veins (hyperlipidemia 1.20; CI₉₅ 1.19 to 1.22; lung cancer 0.81; CI₉₅ 0.76-0.86). Inverse probability of treatment weighting analysis was used to estimate the potential for unmeasured confounders to change risk ratios and supported a possibility of unknown confounders influencing the association between varicose veins and PE and PAD, but the association with DVT remained robust.

Image: PD

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