Association of Varicose Veins With Incident Venous Thromboembolism and Peripheral Artery Disease

Shyue-Luen Chang ^1 2 3, Yau-Li Huang ^1 2 3, Mei-Ching Lee ^1 2 3, Sindy Hu ^1 2 3 4, Yen-Chang Hsiao ⁵, Su-Wei Chang ^6 7, Chee Jen Chang ^8 9, Pei-Chun Chen ^6 10

PMID: 29486040 PMCID: PMC5838574 DOI: 10.1001/jama.2018.0246

Free PMC article

Abstract

Importance: Varicose veins are common but rarely associated with serious health risks. Deep venous thrombosis (DVT), pulmonary embolism (PE), and peripheral artery disease (PAD) are also vascular diseases but associated with serious systemic effects. Little is known about the association between varicose veins and the incidence of other vascular diseases including DVT, PE, and PAD.

Objective: To investigate whether varicose veins are associated with an increased risk of DVT, PE, or PAD.

Design, setting, and participants: A retrospective cohort study using claims data from Taiwan’s National Health Insurance program. Patients aged 20 years and older with varicose veins were enrolled from January 1, 2001-December 31, 2013, and a control group of patients without varicose veins were matched by propensity score. Patients previously diagnosed with DVT, PE, or PAD were excluded. Follow-up ended December 31, 2014.

Exposures: Presence of varicose veins.

Main outcomes and measures: Incidence rates of DVT, PE, and PAD were assessed in people with and without varicose veins. Cox proportional hazards models were used to estimate relative hazards, with the control group as reference.

Results: There were 212 984 patients in the varicose veins group (mean [SD] age, 54.5 [16.0] years; 69.3% women) and 212 984 in the control group (mean [SD] age, 54.3 [15.6] years; 70.3% women). The median follow-up duration was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD for patients with varicose veins, and for the control group, follow-up duration was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD. The varicose veins group had higher incidence rates than the control group for DVT (6.55 vs 1.23 per 1000 person-years [10 360 vs 1980 cases]; absolute risk difference [ARD], 5.32 [95% CI, 5.18-5.46]), for PE (0.48 for the varicose veins group vs 0.28 for the control group per 1000 person-years [793 vs 451 cases]; ARD, 0.20 [95% CI, 0.16-0.24]), and for PAD (10.73 for the varicose veins group vs 6.22 for the control group per 1000 person-years [16 615 vs 9709 cases]; ARD, 4.51 [95% CI, 4.31-4.71]). The hazard ratios for the varicose veins group compared with the control group were 5.30 (95% CI, 5.05-5.56) for DVT, 1.73 (95% CI, 1.54-1.94) for PE, and 1.72 (95% CI, 1.68-1.77) for PAD.

Conclusions and relevance: Among adults diagnosed with varicose veins, there was a significantly increased risk of incident DVT; the findings for PE and PAD are less clear due to the potential for confounding. Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research.

Reference

JAMA. 2018 Feb 27;319(8):807-817. doi: 10.1001/jama.2018.0246.

Presence of varicose veins in cancer patients increases the risk for occurrence of venous thromboembolism

O Königsbrügge ¹, F Lötsch, E-M Reitter, T Brodowicz, C Zielinski, I Pabinger, C Ay

Affiliations expand

PMID: 24112869.  DOI: 10.1111/jth.12408

Free article

Abstract

Background: Cancer patients are at increased risk of venous thromboembolism (VTE).

Objective: We investigated the association of a history of VTE, superficial thrombophlebitis, or the presence of varicose veins with the occurrence of VTE during the course of cancer.

Methods: Cancer patients were recruited in a prospective cohort study, the Vienna Cancer and Thrombosis Study. Patients who had VTE within 3 months before study inclusion were excluded. At study inclusion, history of VTE, history of superficial thrombophlebitis, and presence of varicose veins were recorded. Primary end point was the occurrence of symptomatic VTE. Hazard ratios were obtained using the competing risk analysis according to Fine and Gray.

Results: The cohort consisted of 1270 patients followed over a median of 590 days. A history of VTE was found in 66 patients (5.2%), superficial thrombophlebitis in 79 patients (6.2%), and varicose veins in 160 patients (12.6%). Ninety-eight patients (7.7%) developed VTE during follow-up. The hazard ratios for the risk of VTE in patients with a history of VTE or superficial thrombophlebitis were 1.44 (95% confidence interval: 0.67-3.07) and 1.94 (1.04-3.61), respectively, and 2.01 (1.26-3.21) in those with varicose veins. In multivariable analysis including history of VTE, history of superficial thrombophlebitis, presence of varicose veins, and other patient-related factors, the presence of varicose veins (2.10 [1.29-3.41]) remained significantly associated with an increased risk of VTE.

Conclusion: The presence of varicose veins is associated with an elevated risk of VTE in cancer patients. This clinical parameter could be useful for individual risk assessment of VTE in these patients.

Reference:

J Thromb Haemost. 2013 Nov;11(11):1993-2000. doi: 10.1111/jth.12408.

Varicose veins are a risk factor for deep venous thrombosis in general practice patients

Uwe Müller-Bühl ¹, Rüdiger Leutgeb, Peter Engeser, Edwane N Achankeng, Joachim Szecsenyi, Gunter Laux

Affiliations expand

PMID: 22915533. DOI: 10.1024/0301-1526/a000222

Abstract

Background: The role of varicose veins (VV) as a risk factor for development of deep venous thrombosis (DVT) is still controversial. The aim of this study in primary care was to determine the impact of varicosity as a potential risk factor for developing DVT.

Patients and methods: During the observation period between 01-Jan-2008 and 01-Jan-2011, all cases with VV (ICD code I83.9) and DVT (ICD codes I80.1 – I80.9) were identified out of the CONTENT primary care register (Heidelberg, Germany). The exposure of VV and DVT was based solely on ICD coding without regarding the accuracy of the diagnosis. The covariates age, gender, surgery, hospitalization, congestive heart failure, malignancy, pregnancy, hormonal therapy, and respiratory infection were extracted for each patient. Multivariate binary logistic regression was performed in order to assess potential risk factors for DVT. The SAS procedure “PROC GENMOD” (SAS version 9.2, 64-bit) was parameterised accordingly. A potential cluster effect (patients within practices) was regarded in the regression model.

Results: There were 132 out of 2,357 (5.6 %) DVT episodes among patients with VV compared to 728 out of 80,588 (0.9 %) in the patient cohort without VV (p < 0.0001). An increased risk of DVT was associated with previous DVT (adjusted odds ratio (OR): 9.07, 95 % confidence interval (CI): 7.78 – 10.91), VV (OR 7.33 [CI 6.14 – 8.74]), hospitalization during the last 6 months (OR 1.69 [CI 1.29 – 2.22]), malignancy (OR 1.55 [CI 1.19 – 2.02]), and age (OR 1.02 [CI 1.01 – 1.03]).

Conclusions: There are strong associations between VV and DVT in a general practice population with documented VV. Special medical attention is required for patients with VV, a history of previous venous thromboembolism, comorbid malignancy, and recent hospital discharge, particularly those with a combination of these factors.

Reference:

Vasa. 2012 Sep;41(5):360-5. doi: 10.1024/0301-1526/a000222.

Elevated Venous Thromboembolism Risk Following Colectomy for IBD Is Equal to Those for Colorectal Cancer for Ninety Days After Surgery

Fadwa Ali ¹, Sadeer G Al-Kindi ², Jacqueline J Blank ¹, Carrie Y Peterson ³, Kirk A Ludwig ³, Timothy J Ridolfi ³

PMID: 29420429. DOI: 10.1097/DCR.0000000000001036

Abstract

Background: The risk of postoperative venous thromboembolism is high in patients with colon cancer and IBD. Although The American Society of Colon and Rectal Surgeons suggests posthospital prophylaxis after surgery in patients with colon cancer, there are no such recommendations for patients with IBD.

Objective: This study aims to analyze the incidence and risk factors for postoperative venous thromboembolism.

Design: This was a retrospective review using the Explorys platform.

Settings: Aggregated electronic medical records from 26 major health care systems across the United States from 1999 to 2017 were used for this study.

Patients: Patients who underwent colon surgery were included.

Main outcome measures: Patients were followed up to 90 days postoperatively for deep vein thrombosis and pulmonary embolism.

Results: A total of 75,620 patients underwent colon resections, including 32,020 patients with colon cancer, 9850 patients with IBD, and 33,750 patients with diverticulitis. The 30-day incidence of venous thromboembolism was higher in patients with cancer and IBD than in patients with diverticulitis (2.9%, 3.1%, and 2.4%, p < 0.001 for both comparisons). The 30-day incidence of venous thromboembolism in patients with ulcerative colitis is greater than in patients with Crohn’s disease (4.1% vs 2.1%, p < 0.001). The cumulative incidence of venous thromboembolism increased from 1.2% at 7 days after surgery to 4.3% at 90 days after surgery in patients with cancer, and from 1.3% to 4.3% in patients with IBD. In multivariable analysis, increase in the risk of venous thromboembolism was associated with cancer diagnosis, IBD diagnosis, age ≥60, smoking, and obesity.

Limitations: This study was limited by its retrospective nature and by the use of the aggregated electronic database, which is based on charted codes and contains only limited collateral clinical data.

Conclusions: Because of the elevated and sustained risk of postoperative thromboembolism, patients with IBD, especially ulcerative colitis, might benefit from extended thromboembolism prophylaxis similar to that of patients with colon cancer. See Video Abstract at http://links.lww.com/DCR/A544.

Reference:

Dis Colon Rectum. 2018 Mar;61(3):375-381. doi: 10.1097/DCR.0000000000001036.

The risk of venous thromboembolism during and after hospitalisation in patients with inflammatory bowel disease activity

Thomas P C Chu ¹, Matthew J Grainge ¹, Timothy R Card ^1 2

PMID: 30294897. DOI: 10.1111/apt.15010

Abstract

Background: Inflammatory bowel disease (IBD) increases the risk of venous thromboembolism.

Aims: To determine when patients are at high risk of thromboembolic events, including after major surgery, and to guide timing of thromboprophylaxis.

Methods: Each IBD patient from Clinical Practice Research Datalink, linked with Hospital Episode Statistics, was matched to up to five non-IBD patients in this cohort study. We examined their risk of thromboembolism in hospital and within 6 weeks after leaving hospital, with or without undergoing major surgery, and while ambulant. Hazard ratios were estimated using Cox regression, with adjustment for age, sex, body mass index, smoking and history of malignancy or thromboembolism.

Results: Overall 23 046 IBD patients had a thromboembolic risk 1.74-times (95% CI = 1.55-1.96) higher than 106 795 non-IBD patients. Among ambulant patients, the thromboembolic risk was raised during acute (hazard ratio = 3.94, 2.79-5.57) or chronic disease activity (3.97, 2.90-5.45) but their absolute risk remained below 5/1000 person-years. The hazard ratio for thromboembolism among in-patients not undergoing major surgery was 1.13 (0.63-2.02), compared to 2.43 (1.20-4.92) among surgical patients, with a near doubling of absolute risk associated with surgery (59.5/1000 person-years, compared with 31.1 without surgery). The absolute risk remained elevated within 6 weeks after leaving hospital (18.6/1000 person-years in IBD patients after surgery).

Conclusions: IBD patients are at an increased risk of venous thromboembolism. Absolute risks are raised during active disease, when in hospital, and after leaving hospital following major surgery.

Reference:

Aliment Pharmacol Ther. 2018 Nov;48(10):1099-1108. doi: 10.1111/apt.15010. Epub 2018 Oct 8

See full article for a thorough discussion on leg swelling.

https://journals.sagepub.com/doi/full/10.1177/1358863X16672576

Reference:
Vasc Med 2016 Dec;21(6):562-564. doi: 10.1177/1358863X16672576. Epub 2016 Oct 12.

The outpatient with unilateral leg swelling

G J Merli ¹, J Spandorfer

PMID: 7877400. DOI: 10.1016/s0025-7125(16)30077-3

Abstract

Approaching the patient with unilateral leg swelling presents a challenge to the physician in ambulatory practice. Contributing to the difficulty is the lack of studies that have assessed a population of patients presenting with unilateral leg swelling. The purpose of this article is to discuss unilateral leg swelling with respect to the chronicity of the presentation and the most common differential diagnoses based on a review of the current literature and personal clinical experience.

Reference:

Med Clin North Am. 1995 Mar;79(2):435-47. doi: 10.1016/s0025-7125(16)30077-3.

Impact of incident myocardial infarction on the risk of venous thromboembolism: the Tromsø Study

L B Rinde ¹, C Lind ¹, B Småbrekke ¹, I Njølstad ^1 2, E B Mathiesen ^1 3, T Wilsgaard ², M-L Løchen ², E M Hald ^1 4, A Vik ^1 4, S K Braekkan ^1 4, J-B Hansen ^1 4

PMID: 27061154. DOI: 10.1111/jth.13329

Abstract

Essentials Registry-based studies indicate a link between arterial- and venous thromboembolism (VTE). We studied this association in a cohort with confounder information and validated outcomes. Myocardial infarction (MI) was associated with a 4.8-fold increased short-term risk of VTE. MI was associated with a transient increased risk of VTE, and pulmonary embolism in particular.

Summary: Background Recent studies have demonstrated an association between venous thromboembolism (VTE) and arterial thrombotic diseases. Objectives To study the association between incident myocardial infarction (MI) and VTE in a prospective population-based cohort. Methods Study participants (n = 29 506) were recruited from three surveys of the Tromsø Study (conducted in 1994-1995, 2001-2002, and 2007-2008) and followed up to 2010. All incident MI and VTE events during follow-up were recorded. Cox regression models with age as the time scale and MI as a time-dependent variable were used to calculate hazard ratios (HRs) of VTE adjusted for sex, body mass index, blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity, and education level. Results During a median follow-up of 15.7 years, 1853 participants experienced an MI and 699 experienced a VTE. MI was associated with a 51% increased risk of VTE (HR 1.51; 95% confidence interval [CI] 1.08-2.10) and a 72% increased risk of pulmonary embolism (PE) (HR 1.72; 95% CI 1.07-2.75), but not significantly associated with the risk of deep vein thrombosis (DVT) (HR 1.36; 95% CI 0.86-2.15). The highest risk estimates for PE were observed during the first 6 months after the MI (HR 8.49; 95% CI 4.00-18.77). MI explained 6.2% of the PEs in the population (population attributable risk) and 78.5% of the PE risk in MI patients (attributable risk). Conclusions Our findings indicate that MI is associated with a transient increased VTE risk, independently of traditional atherosclerotic risk factors. The risk estimates were particularly high for PE.

Reference:

Thromb Haemost. 2016 Jun;14(6):1183-91. doi: 10.1111/jth.13329. Epub 2016 May 10.

Heart disease may be a risk factor for pulmonary embolism without peripheral deep venous thrombosis

Henrik T Sørensen ¹, Erzsebet Horvath-Puho, Timothy L Lash, Christian F Christiansen, Raffaele Pesavento, Lars Pedersen, John A Baron, Paolo Prandoni

PMID: 21900083. DOI: 10.1161/CIRCULATIONAHA.111.025627

Abstract

Background: Heart diseases increase the risk of arterial embolism; whether they increase the risk of pulmonary embolism without peripheral venous thrombosis is less certain.

Methods and results: We conducted a nationwide, population-based case-control study in Denmark using patients diagnosed with pulmonary embolism and/or deep venous thrombosis between 1980 and 2007. We computed odds ratios to estimate relative risks associating preceding heart disease with pulmonary embolism, pulmonary embolism and deep venous thrombosis, or deep venous thrombosis alone. In this study, 45,282 patients had pulmonary embolism alone, 4680 had pulmonary embolism and deep venous thrombosis, and 59,790 had deep venous thrombosis alone; 541,561 were population controls. Myocardial infarction and heart failure in the preceding 3 months conferred high risks of apparently isolated pulmonary embolism (odds ratio, 43.5 [95% confidence interval (CI), 39.6-47.8] and 32.4 [95% CI, 29.8-35.2], respectively), whereas the risks of combined pulmonary embolism and deep venous thrombosis (19.7 [95% CI, 16.0-24.2] and 22.1 [95% CI, 18.7-26.0], respectively) and deep venous thrombosis alone (9.6 [95% CI, 8.6-10.7] and 12.7 [95% CI, 11.6-13.9], respectively) were lower. Left-sided valvular disease was associated with an odds ratio of 13.5 (95% CI, 11.3-16.1), whereas the odds ratio was 74.6 (95% CI, 28.4-195.8) for right-sided valvular disease. Restricting the analysis to cases diagnosed after 2000 led to lower risk estimates but the same overall pattern.

Conclusion: Heart diseases increase the near-term risk for pulmonary embolism not associated with diagnosed peripheral vein thrombosis.

Circulation. 2011 Sep 27;124(13):1435-41. doi: 10.1161/CIRCULATIONAHA.111.025627.Epub 2011 Sep 6.

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism

Christina L Fanola ¹, Faye L Norby ², Amil M Shah ³, Patricia P Chang ⁴, Pamela L Lutsey ², Wayne D Rosamond ⁴, Mary Cushman ⁵, Aaron R Folsom ²

PMID: 31948643. PMCID: PMC7262575. DOI: 10.1016/j.jacc.2019.10.058

Abstract

Background: Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown.

Objectives: In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed.

Methods: During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE.

Results: Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE.

Conclusions: In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

Reference:

J Am Coll Cardiol. 2020 Jan 21;75(2):148-158. doi: 10.1016/j.jacc.2019.10.058

Classification of heart failure in the atherosclerosis risk in communities (ARIC) study: a comparison of diagnostic criteria

Wayne D Rosamond ¹, Patricia P Chang, Chris Baggett, Anna Johnson, Alain G Bertoni, Eyal Shahar, Anita Deswal, Gerardo Heiss, Lloyd E Chambless

PMID: 22271752. PMCID: PMC3326579. DOI: 10.1161/CIRCHEARTFAILURE.111.963199

Abstract

Background: Population-based research on heart failure (HF) is hindered by lack of consensus on diagnostic criteria. Framingham (FRM), National Health and Nutrition Examination Survey (NHANES), Modified Boston (MBS), Gothenburg (GTH), and International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) code criteria, do not differentiate acute decompensated heart failure (ADHF) from chronic stable HF. We developed a new classification protocol for identifying ADHF in the Atherosclerosis Risk in Communities (ARIC) Study and compared it with these other schemes.

Methods and results: A sample of 1180 hospitalizations with a patient address in 4 study communities and eligible discharge codes were selected. After assessing whether the chart contained evidence of possible HF signs, 705 were fully abstracted. Two independent reviewers classified each case as ADHF, chronic stable HF, or no HF, using ARIC classification guidelines. Fifty-nine percent of cases met ARIC criteria for ADHF and 13.9% and 27.1% were classified as chronic stable HF or no HF, respectively. Among events classified as HF by FRM criteria, 68.4% were validated as ADHF, 9.6% as chronic stable HF, and 21.9% as no HF. However, 92.5% of hospitalizations with a primary ICD-9-CM 428 “heart failure” code were validated as ADHF. Sensitivities of comparison criteria to classify ADHF ranged from 38-95%, positive predictive values from 62-92%, and specificities from 19-96%.

Conclusions: Although comparison criteria for classifying HF were moderately sensitive in identifying ADHF, specificity varied when applied to a randomly selected set of suspected HF hospitalizations in the community.

Reference:

Circ Heart Fail. 2012 Mar 1;5(2):152-9. doi: 10.1161/CIRCHEARTFAILURE.111.963199. Epub 2012 Jan 23.

Risk factors and clinical impact of postoperative symptomatic venous thromboembolism

Chethan Gangireddy ¹, John R Rectenwald, Gilbert R Upchurch, Thomas W Wakefield, Shukri Khuri, William G Henderson, Peter K Henke

PMID: 17264013. DOI: 10.1016/j.jvs.2006.10.034

Abstract

Background: Although common risk factors for venous thromboembolism (VTE) are well known, little data exist concerning the clinical impact of VTE in postoperative patients outside of controlled studies. This study evaluated prospective perioperative demographic and clinical variables associated with occurrence of postoperative symptomatic VTE.

Methods: Demographic and clinical data were collected on surgical patients undergoing nine common general, vascular, and orthopedic operations presenting to the Veterans Health Administration Hospitals between 1996 and 2001 as part of the National Surgical Quality Improvement Program (NSQIP). The association between covariates and the incidence of postoperative symptomatic VTE (includes deep venous thrombosis and pulmonary embolism) was assessed using bivariable and multivariable regression.

Results: Complete demographic and clinical information for analysis were available for 75,771 patients. The mean patient age was 65 years, and 96.6% were men. Major comorbidities included diabetes mellitus (DM), 25%; chronic obstructive pulmonary disease (COPD), 18.3%; and congestive heart failure (CHF), 3.9%. Symptomatic VTE was diagnosed in 805 patients (0.68%), varied significantly with procedure (0.14% for carotid endarterectomy vs 1.34% for total hip arthroplasty), and was associated with increased 30-day mortality (16.9% vs 4.4%, P < .0001). The incidence of VTE did not decline substantially between 1996 and 2001 (0.72% vs 0.68%). Preoperative factors associated with symptomatic VTE were older age, male gender, corticosteroid use, COPD, recent weight loss, disseminated cancer, low albumin, and low hematocrit (all P < .01) but not DM. Postoperative factors associated with VTE were myocardial infarction (MI), blood transfusion (>4 units), coma, pneumonia, and urinary tract infection (UTI), whereas those with hemodialysis-dependent renal failure were less likely to experience VTE (all P < .01). In multivariable analysis, adjusting for age and the variables significant by bivariable analysis, the strongest positive predictors of symptomatic VTE included UTI (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3 to 2.5), acute renal insufficiency (OR, 1.9; 95% CI, 1.1 to 3.2), postoperative transfusion (OR, 2.3; 95% CI, 1.4 to 3.7), perioperative MI (OR, 2.4; 95% CI, 1.5 to 3.9), and pneumonia (OR, 2.7; 95% CI, 2.1 to 3.5). In contrast, hemodialysis (OR, 0.3; 95% CI, 0.07 to 0.71), DM (OR, 0.75; 95% CI, 0.61 to 0.93), and higher preoperative albumin levels (OR, 0.8; 95% CI, 0.74 to 0.96, per mg/dL change) were protective from symptomatic VTE.

Conclusions: Although the overall incidence of symptomatic VTE is low in surgical patients, it is associated with significantly increased 30-day mortality. In addition to previously recognized risk factors, patients who have postoperative complications of an infectious nature, bleeding, or MI are at particular risk.

Reference:

J Vasc Surg. 2007 Feb;45(2):335-341; discussion 341-2. doi: 10.1016/j.jvs.2006.10.034.

Preoperative Pneumonia and Postoperative Venous Thrombosis: A Cohort Study of 427,656 Patients Undergoing Major General Surgery

Karim Z Masrouha ¹, Khaled M Musallam ^2 3, Frits R Rosendaal ⁴, Jamal J Hoballah ⁵, Faek R Jamali ⁶

PMID: 26817651. DOI: 10.1007/s00268-016-3409-1

Abstract

Background: The literature is sparse regarding the association between pneumonia and venous thrombosis in surgical patients. The aim of this study was to investigate the risk of postoperative venous thrombosis in patients who fit the criteria for preoperative pneumonia using data from the ongoing American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database while adjusting for potential confounders.

Methods: This is a cohort study using data from the ACS NSQIP database participating sites from 2008 (211 sites) and 2009 (237 sites). 427,656 patients undergoing major general surgery were included. The 30-day risk of postoperative venous thrombosis including deep vein thrombosis (DVT) and pulmonary embolism (PE) was evaluated in patients with preoperative pneumonia diagnosed before undergoing major general surgery.

Results: Patients with preoperative pneumonia had a higher incidence of both 30-day DVT and PE than patients without preoperative pneumonia. After adjusting for all potential confounders, the effect estimates for the association between preoperative pneumonia and venous thrombosis were DVT, OR: 1.67 (95% CI 1.32-2.11) and PE, OR: 2.18 (95% CI 1.48-3.22).

Conclusions: A large, multicenter database of surgical patients showed that preoperative pneumonia may increase risk for developing venous thrombosis. This adds to our understanding of risk factors for venous thrombosis and suggests a potential benefit of diagnosing preoperative pneumonia in patients undergoing major general surgery.

Reference:

World J Surg. 2016 Jun;40(6):1288-94. doi: 10.1007/s00268-016-3409-1.

Reference:

Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O’Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019 Mar 5;139(10):e56-e528. doi: 10.1161/CIR.0000000000000659. Erratum in: Circulation. 2020 Jan 14;141(2):e33. PMID: 30700139.

Paradoxical embolism

Stephan Windecker ¹, Stefan Stortecky ², Bernhard Meier ²

PMID: 25060377. DOI: 10.1016/j.jacc.2014.04.063

Abstract

Paradoxical embolism is an important clinical entity among patients with venous thromboembolism in the presence of intracardiac or pulmonary shunts. The clinical presentation is diverse and potentially life-threatening. Although the serious nature and complications of paradoxical embolism are recognized, the disease entity is still rarely considered and remains under-reported. This paper provides an overview on the different clinical manifestations of paradoxical embolism, describes the diagnostic tools for the detection of intracardiac and pulmonary shunts, reviews therapeutic options, and summarizes guideline recommendations for the secondary prevention of paradoxical embolism.

Reference:
J Am Coll Cardiol. 2014 Jul 29;64(4):403-15. doi: 10.1016/j.jacc.2014.04.063.

Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report

Gregory Y H Lip ¹, Amitava Banerjee ², Giuseppe Boriani ³, Chern En Chiang ⁴, Ramiz Fargo ⁵, Ben Freedman ⁶, Deirdre A Lane ⁷, Christian T Ruff ⁸, Mintu Turakhia ⁹, David Werring ¹⁰, Sheena Patel ¹¹, Lisa Moores ¹²

PMID: 30144419. DOI: 10.1016/j.chest.2018.07.040

Abstract

Background: The risk of stroke is heterogeneous across different groups of patients with atrial fibrillation (AF), being dependent on the presence of various stroke risk factors. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios.

Methods: Systematic literature reviews were conducted to identify relevant articles published from the last formal search perfomed for the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). The overall quality of the evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. Graded recommendations and ungraded consensus-based statements were drafted, voted on, and revised until consensus was reached.

Results: For patients with AF without valvular heart disease, including those with paroxysmal AF, who are at low risk of stroke (eg, CHA₂DS₂-VASc [congestive heart failure, hypertension, age ≥ 75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female)] score of 0 in males or 1 in females), we suggest no antithrombotic therapy. The next step is to consider stroke prevention (ie, oral anticoagulation therapy) for patients with 1 or more non-sex CHA₂DS₂-VASc stroke risk factors. For patients with a single non-sex CHA₂DS₂-VASc stroke risk factor, we suggest oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel; and for those at high risk of stroke (eg, CHA₂DS₂-VASc ≥ 2 in males or ≥ 3 in females), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest using a non-vitamin K antagonist oral anticoagulant drug rather than adjusted-dose vitamin K antagonist therapy. With the latter, it is important to aim for good quality anticoagulation control with a time in therapeutic range > 70%. Attention to modifiable bleeding risk factors (eg, uncontrolled BP, labile international normalized ratios, concomitant use of aspirin or nonsteroidal antiinflammatory drugs in an anticoagulated patient, alcohol excess) should be made at each patient contact, and HAS-BLED (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding history or predisposition, labile international normalized ratio, elderly (0.65), drugs/alcohol concomitantly [1 point each]) score used to assess the risk of bleeding where high risk patients (≥ 3) should be reviewed and followed up more frequently.

Conclusions: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF with ≥1 non-sex CHA₂DS₂-VASc stroke risk factor(s).

Reference:

Chest. 2018 Nov;154(5):1121-1201. doi: 10.1016/j.chest.2018.07.040.Epub 2018 Aug 22.

Insights from thrombi retrieved in stroke due to large vessel occlusion

Marco Bacigaluppi ¹, Aurora Semerano ¹, Giorgia Serena Gullotta ¹, Davide Strambo ^1 2

PMID: 31213164. PMCID: PMC6681524. DOI: 10.1177/0271678X19856131

Abstract

The recent advances of endovascular procedures to treat stroke due to large cerebral vessel occlusion have made it possible to analyze the retrieved thrombus material. Analysis of cerebral thrombi is emerging as a relevant opportunity to complement the diagnostic workup of etiology, to develop new lytic approaches and to optimize the acute treatment of stroke due to large vessel occlusion. Nonetheless, retrieved thrombi are frequently discarded since their informative potential is often neglected and standards are missing. This review provides an overview of the current knowledge and expanding research relating to thrombus composition analysis in large vessel occlusions. We first discuss the heterogeneity of thrombogenic factors that underlie the thrombotic formation in stroke and its implications to identify stroke etiology and thrombus age. Further, we show that understanding structural characteristics of thrombus is pivotal for the development of new-targeted lytic therapies as well as to improve, through thrombus modeling, the development of thrombectomy devices. Finally, we discuss the on-going attempts to identify a signature of thrombus composition indirectly through imaging and peripheral blood biomarkers, which might in future assist treatment decision-making as well as secondary prevention. Thrombus analysis might contribute to the advancement and optimization of personalized stroke treatments.

Reference:

J Cereb Blood Flow Metab. 2019 Aug;39(8):1433-1451.doi: 10.1177/0271678X19856131. Epub 2019 Jun 18.

Does ambulation modify venous thromboembolism risk in acutely ill medical patients?

Alpesh N Amin ¹, Frederick Girard, Meyer M Samama

PMID: 20838741. DOI: 10.1160/TH10-04-0236

Abstract

In the US, ambulatory status is often a criterion for stopping prophylaxis for venous thromboembolism (VTE). In an analysis of the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial, ambulatory status was assessed as outcome and patients grouped accordingly for further analysis. Rates of VTE and bleeding were evaluated. Using multivariate logistic regression, the relationships between thromboprophylaxis, VTE risk, and ambulatory status were assessed. Ambulatory status was reached in 607/1,084 patients, in a mean time of 4.4 days. Thromboprophylaxis was provided for 7.3 and 7.7 days in the ambulatory and non-ambulatory groups. Although VTE rates were lower in ambulatory patients, enoxaparin 40 mg once daily significantly reduced the risk of VTE vs. placebo in ambulatory (3.3% vs. 10.6%; relative risk [RR] = 0.31; 95% confidence interval [CI], 0.13-0.78; p=0.008) and non-ambulatory patients (9.0% vs. 19.7%; RR = 0.46; 95% CI, 0.23-0.91; p=0.02). Major bleeding was not significantly different between enoxaparin and placebo in either group. By multivariate regression analysis, VTE risk in ambulatory patients was lower with enoxaparin vs. placebo (odds ratio [OR] = 0.28; 95% CI, 0.11-0.74; p=0.01), but higher in patients with a history of VTE (OR = 3.74; 95% CI, 1.59-8.84; p=0.003) or cancer (OR = 2.12; 95% CI, 1.00-4.48; p=0.049). Despite timely mobilisation, patients who become ambulatory are at VTE risk and experience a significant risk reduction with enoxaparin 40 mg. Therefore, it is essential that ambulatory patients receive recommended thromboprophylaxis.

Reference:

Thromb Haemost. 2010 Nov;104(5):955-61. doi: 10.1160/TH10-04-0236. Epub 2010 Sep 13.

Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism

D Nauffal ¹, M Ballester, R Lopez Reyes, D Jiménez, R Otero, R Quintavalla, M Monreal, RIETE Investigators

Collaborators,

PMID: 22726525. DOI: 10.1111/j.1538-7836.2012.04829.x

Abstract

Background: The influence of recent immobilization or surgery on mortality in patients with pulmonary embolism (PE) is not well known.

Methods: We used the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) data to compare the 3-month mortality rate in patients with PE, with patients categorized according to the presence of recent immobilization, recent surgery, or neither.

Results: Of 18,028 patients with PE, 4169 (23%) had recent immobilization, 2212 (12%) had recent surgery, and 11,647 (65%) had neither. The all-cause mortality was 10.0% (95% confidence interval [CI] 9.5-10.4), and the PE-related mortality was 2.6% (95% CI 2.4-2.9). One in every two patients who died from PE had recent immobilization (43%) or recent surgery (6.7%). Only 25% of patients with immobilization had received prophylaxis, as compared with 65% of the surgical patients. Fatal PE was more common in patients with recent immobilization (4.9%; 95% CI 4.3-5.6) than in those with surgery (1.4%; 95% CI 1.0-2.0) or those with neither (2.1%; 95% CI 1.8-2.3). On multivariate analysis, patients with immobilization were at increased risk for fatal PE (odds ratio 2.2; 95% CI 1.8-2.7), with no differences being seen between patients immobilized in hospital or in the community.

Conclusions: Forty-three per cent of patients dying from PE had recent immobilization for ≥4 days. Many of these deaths could have been prevented.

Reference:

J Thromb Haemost. 2012 Sep;10(9):1752-60. doi: 10.1111/j.1538-7836.2012.04829.x.

The impact of risk assessment on the implementation of venous thromboembolism prophylaxis in foot and ankle surgery

Nikiforos Pandelis Saragas ¹, Paulo Norberto Faria Ferrao ², Evanthia Saragas ³, Barry F Jacobson ⁴

PMID: 24796824. DOI: 10.1016/j.fas.2013.11.002

Abstract

Background: The purpose of this prospective study was to determine whether the more frequently quoted procedure and patient specific risk factors have any impact in the implementation of venous thromboembolism (VTE) prophylaxis following foot and ankle surgery.

Methods: Two hundred and sixteen patients were included in the study. A variety of operative procedures was carried out with the common denominator being a below knee cast for at least 4 weeks and nonweightbearing for an average of 6 weeks in 130 patients. The remainder of the patients (88) had hallux surgery not requiring a cast and were allowed to weightbear. No patient received any form of thromboprophylaxis postoperatively. All patients were subjected to compression ultrasonography for deep vein thrombosis (DVT) between 2 and 6 weeks postoperatively.

Results: There was a 5.09% incidence of VTE (0.9% pulmonary embolism) overall. As no VTE (neither DVT nor pulmonary embolus) developed in the hallux subgroup, i.e. patients not requiring immobilization and were allowed to weightbear, the incidence of VTE in the cast/nonweightbearing group was 8.46%. The results are descriptive and only statistically analyzed where possible, as the sample size of the VTE group was small. There was no significant difference in number of risk factors and no association between gender in the VTE and non VTE groups. 90.9% of patients in the VTE group had a total risk factor score of 5 or more and 73.7% of patients in the non VTE group had a total risk factor score of 5 or more. The average timing to the diagnosis of VTE in this current study was 33.1 days.

Conclusions: In view of the unacceptable incidence of VTE and the average total risk factor score of 5 or more (for which thromboprophylaxis is recommended) in the majority of the patients, the authors feel that the routine use of thromboprophylaxis in foot and ankle surgery requiring nonweightbearing in combination with short leg cast immobilization, is warranted. This prophylaxis should continue until the patient regains adequate mobility either by weightbearing (in or out of the cast) or removal of cast immobilization (weightbearing or nonweightbearing), usually between 28 and 42 days.

Reference:

Foot Ankle Surg. 2014 Jun;20(2):85-9. doi: 10.1016/j.fas.2013.11.002. Epub 2013 Nov 14.

Pharmacological thromboprophylaxis to prevent venous thromboembolism in patients with temporary lower limb immobilization after injury: systematic review and network meta-analysis

Daniel Horner ^1 2, John W Stevens ², Abdullah Pandor ², Tim Nokes ³, Jonathan Keenan ³, Kerstin de Wit ⁴, Steve Goodacre ²

PMID: 31654551. PMCID: PMC7028118. DOI: 10.1111/jth.14666

Abstract

Background: Thromboprophylaxis has the potential to reduce venous thromboembolism (VTE) following lower limb immobilization resulting from injury.

Objectives: We aimed to estimate the effectiveness of thromboprophylaxis, compare different agents, and identify any factors associated with effectiveness.

Methods: We undertook a systematic review and network meta-analysis (NMA) of randomized trials reporting VTE or bleeding outcomes that compared thromboprophylactic agents with each other or to no pharmacological prophylaxis, for this indication. An NMA was undertaken for each outcome or agent used, and a series of study-level network meta-regressions examined whether population characteristics, type of injury, treatment of injury, or duration of thromboprophylaxis were associated with treatment effect.

Results: Data from 6857 participants across 13 randomized trials showed that, compared with no treatment, low molecular weight heparin (LMWH) reduced the risk of any VTE (odds ratio [OR]: 0.52; 95% credible interval [CrI]: 0.37-0.71), clinically detected deep vein thrombosis (DVT) (OR: 0.39; 95% CrI: 0.12-0.94) and pulmonary embolism (PE) (OR: 0.16; 95% CrI: 0.01-0.74), whereas fondaparinux reduced the risk of any VTE (OR: 0.13; 95% CrI: 0.05-0.30) and clinically detected DVT (OR: 0.10; 95% CrI: 0.01-0.86), with inconclusive results for PE (OR: 0.40; 95% CrI: 0.01-7.53).

Conclusions: Thromboprophylaxis with either fondaparinux or LMWH appears to reduce the odds of both asymptomatic and clinically detected VTE in people with temporary lower limb immobilization following an injury. Treatment effects vary by outcome and are not always conclusive. We were unable to identify any treatment effect modifiers other than thromboprophylactic agent used.

J Thromb Haemost. 2020 Feb;18(2):422-438. doi: 10.1111/jth.14666.Epub 2019 Dec 1.

The effect of ankle joint immobilization on lower limb venous flow

Johnathan D Craik ¹, Amanda Clark ², James Hendry ², Andrea H Sott ², Paul D Hamilton ²

PMID: 25249319. DOI: 10.1177/1071100714552823

Abstract

Background: Below-knee cast immobilization is associated with an increased risk of developing deep vein thrombosis secondary to venous stasis. We investigated the effect of weight-bearing in a below-knee cast or pneumatic walking boot on lower limb venous blood flow.

Methods: Duplex ultrasonography was used to measure venous blood flow in the popliteal vein of 10 healthy volunteers. Venous blood flow was measured while at rest, ambulating non-weight-bearing, partial weight-bearing, and full weight-bearing. Measurements were performed without ankle joint immobilization, with the ankle immobilized in a neutral cast, and with the ankle immobilized in a pneumatic walking boot in both neutral and equinus.

Results: There was no significant reduction in venous blood flow measurements between full weight-bearing without ankle joint immobilization and full weight-bearing in a neutral cast or neutral pneumatic walking boot. However, venous blood flow was reduced when partial weight-bearing (50%) and when full weight-bearing in a pneumatic walking boot in equinus.

Conclusion: These results demonstrate that venous blood flow returned to normal levels when the subjects were permitted to fully bear weight in below-knee casts or walking boots, provided that the ankle joint was not in equinus.

Clinical relevance: Weight-bearing status and ankle joint position should be appreciated during decisions for the provision of chemical thromboprophylaxis.

Reference:

Foot Ankle Int.  2015 Jan;36(1):18-23.

 doi: 10.1177/1071100714552823. Epub 2014 Sep 23.

Prevention of postoperative deep venous thrombosis and pulmonary emboli with combined modalities

M Borow, H J Goldson

PMID: 6195948

Abstract

Worldwide statistics reveal that 25 to 40 per cent of patients who are over the age of 40 years and operated on for 1 or more hours will develop a deep venous thrombosis (DVT). The studies reviewed in this paper were performed to evaluate several modalities and compare their effectiveness in preventing DVT in postoperative patients. In the first study, five modalities plus a control group were evaluated in 562 patients from five surgical specialties. The incidence of DVT in the control group was 35 per cent. Though most of the pharmacologic agents were effective in reducing the incidence of DVT, the antistasis devices (gradient elastic stockings and intermittent pneumatic compression) were most effective. The purpose of the second study was to evaluate the effectiveness of combining a pharmacologic drug with an antistasis modality. Deep venous thrombosis was virtually eliminated in this group of 328 patients. There was only a 1.5 per cent incidence of DVT in the treated population as compared to a 26.8 per cent incidence in the control group. Thus, it seems that combining one antistasis and one pharmacologic agent greatly reduces the incidence of lower extremity thrombi. I-125 fibrinogen scanning was the most sensitive test in detecting DVT and had an accuracy of 97 per cent.

Reference:

Am Surg. 1983 Nov;49(11):599-605.

Risk factors for venous thromboembolism

Frederick A Anderson Jr ¹, Frederick A Spencer

PMID: 12814980 DOI: 10.1161/01.CIR.0000078469.07362.E6

Abstract

Until the 1990s, venous thromboembolism (VTE) was viewed primarily as a complication of hospitalization for major surgery (or associated with the late stage of terminal illness). However, recent trials in patients hospitalized with a wide variety of acute medical illnesses have demonstrated a risk of VTE in medical patients comparable with that seen after major general surgery. In addition, epidemiologic studies have shown that between one quarter and one half of all clinically recognized symptomatic VTEs occur in individuals who are neither hospitalized nor recovering from a major illness. This expanding understanding of the population at risk challenges physicians to carefully examine risk factors for VTE to identify high-risk patients who could benefit from prophylaxis. Factors sufficient by themselves to prompt physicians to consider VTE prophylaxis include major surgery, multiple trauma, hip fracture, or lower extremity paralysis because of spinal cord injury. Additional risk factors, such as previous VTE, increasing age, cardiac or respiratory failure, prolonged immobility, presence of central venous lines, estrogens, and a wide variety of inherited and acquired hematological conditions contribute to an increased risk for VTE. These predisposing factors are seldom sufficient by themselves to justify the use of prophylaxis. Nevertheless, individual risk factors, or combinations thereof, can have important implications for the type and duration of appropriate prophylaxis and should be carefully reviewed to assess the overall risk of VTE in each patient.

Reference:

Circulation. 2003 Jun 17;107(23 Suppl 1):I9-16. doi: 10.1161/01.CIR.0000078469.07362.E6.

Joint replacement: https://pubmed.ncbi.nlm.nih.gov/11114314/

Abstract

Background: Recent studies have shown that symptomatic venous thromboembolism after total hip arthroplasty most commonly develops after the patient is discharged from the hospital. Risk factors associated with these symptomatic thromboembolic events are not well defined.

Methods: Using administrative data from the California Medicare records for 1993 through 1996, we identified 297 patients 65 years of age or older who were rehospitalized for thromboembolism within three months after total hip arthroplasty. We compared demographic, surgical, and medical variables potentially associated with the development of thromboembolism in these patients and 592 unmatched controls.

Results: A total of 89.6 percent of patients with thromboembolism and 93.8 percent of control patients were treated with pneumatic compression, warfarin, enoxaparin, or unfractionated heparin, alone or in combination. In addition, 22.2 percent and 29.7 percent, respectively, received warfarin after discharge. A body-mass index (the weight in kilograms divided by the square of the height in meters) of 25 or greater was associated with rehospitalization for thromboembolism, with an odds ratio of 2.5 (95 percent confidence interval, 1.8 to 3.4). In a multivariate model, the only prophylactic regimens associated with a reduced risk of thromboembolism were pneumatic compression in patients with body-mass indexes of less than 25 (odds ratio, 0.3; 95 percent confidence interval, 0.2 to 0.6) and warfarin treatment after discharge (odds ratio, 0.6; 95 percent confidence interval, 0.4 to 1.0).

Conclusions: In patients who underwent total hip arthroplasty, a body-mass index of 25 or greater was associated with subsequent hospitalization for thromboembolism. Pneumatic compression in patients with a body-mass index of less than 25 and prophylaxis with warfarin after discharge were independently protective against thromboembolism.

Pills: https://pubmed.ncbi.nlm.nih.gov/12624633/

Abstract

Deep vein thrombosis (DVT) is a common disease with an annual incidence of about 1 in 1000. Many risk factors have already been studied, both genetic and acquired. It is unclear whether obesity affects thrombotic risk in unselected patients. Obesity is common, with a prevalence of 20-25% and may therefore have a considerable impact on the overall incidence of thrombosis. We evaluated the risk of thrombosis due to overweight and obesity using data from a large population-based case-control study. Four hundred and fifty-four consecutive patients with a first episode of objectively diagnosed thrombosis from three Anticoagulation Clinics in the Netherlands were enrolled in a case-control study. Controls were matched on age and sex to patients and were introduced by the patients. All patients completed a standard questionnaire and interview, with weight and height measured under standard conditions. The associations of obesity with clotting factor levels were studied to investigate possible mechanisms. Obesity (BMI >/=30 kg/m(2)) increased the risk of thrombosis twofold (CI95: 1.5 to 3.4), adjusted for age and sex. Obese individuals had higher levels of factor VIII and factor IX, but not of fibrinogen. The effect on risk of obesity was not changed after adjustment for coagulation factors levels (fibrinogen, F VIII, F IX, D-dimer). The relative risk estimates were similar in different age groups and in both sexes, indicating a larger absolute effect in older age groups. Evaluation of the combined effect of obesity and oral contraceptive pills among women aged 15-45 revealed that oral contraceptives further increased the effect of obesity on the risk of thrombosis, leading to 10-fold increased risk amongst women with a BMI greater than 25 kg/m(2) who used oral contraceptives. Obesity is a risk factor for deep vein thrombosis. Among women with a BMI greater than 25 kg/m(2) the synergistic effect with oral contraceptives should be considered when prescribing these.