Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies

doi:10.1161/CIRCULATIONAHA.116.024507

Meta-Analysis

. 2017 Jan 3;135(1):7-16.

doi: 10.1161/CIRCULATIONAHA.116.024507. Epub 2016 Nov 9.

Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies

Bakhtawar K Mahmoodi¹, Mary Cushman², Inger Anne Næss², Matthew A Allison², Willem J Bos², Sigrid K Brækkan², Suzanne C Cannegieter², Ron T Gansevoort², Philimon N Gona², Jens Hammerstrøm², John-Bjarne Hansen², Susan Heckbert², Anders G Holst², Susan G Lakoski², Pamela L Lutsey², JoAnn E Manson², Lisa W Martin², Kunihiro Matsushita², Karina Meijer², Kim Overvad², Eva Prescott², Marja Puurunen², Jacques E Rossouw², Yingying Sang², Marianne T Severinsen², Jur Ten Berg², Aaron R Folsom², Neil A Zakai²

Affiliations

¹ From Department of Cardiology and Internal Medicine, Sint Antonius Hospital, Nieuwegein, The Netherlands (B.K.M., W.J.B., J.t.B.); Department of Haematology, University Medical Center Groningen, University of Groningen, The Netherlands (B.K.M., K. Meijer); Departments of Medicine and Pathology, University of Vermont, Burlington (M.C., N.A.Z.); Department of Hematology, Trondheim University Hospital, Norway (I.A.N., J.H.); Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.); K. G. Jebsen-Thrombosis Research and Expertise Center, Department of Clinical Medicine, University of Tromsø, Norway (S.K.B., J.- B.H.); Department of Clinical Epidemiology, Leiden University Medical Center, University of Leiden, The Netherlands (S.C.C.); Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands (R.T.G.); Department of Exercise and Health Sciences, University of Massachusetts, Boston (P.N.G.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.H.); Laboratory for Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark (A.G.H.); Department of Clinical Cancer Prevention and Cardiology, University of Texas MD Anderson Cancer Center, Houston (S.G.L.); Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (P.L.L., A.R.F.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.); Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC (L.W.M.); Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (K. Matsushita, Y.S.); Department of Public Health, Section for Epidemiology, Aarhus University, and Department of Cardiology, Aalborg University Hospital, Denmark (K.O.); Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Denmark (E.P.); Framingham Heart Study, Boston University School of Medicine, MA (M.P.); National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.); and Department of Hematology, Aalborg University Hospital, Denmark (M.T.S.). b.k.mahmoodi@umcg.nl.
² From Department of Cardiology and Internal Medicine, Sint Antonius Hospital, Nieuwegein, The Netherlands (B.K.M., W.J.B., J.t.B.); Department of Haematology, University Medical Center Groningen, University of Groningen, The Netherlands (B.K.M., K. Meijer); Departments of Medicine and Pathology, University of Vermont, Burlington (M.C., N.A.Z.); Department of Hematology, Trondheim University Hospital, Norway (I.A.N., J.H.); Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.); K. G. Jebsen-Thrombosis Research and Expertise Center, Department of Clinical Medicine, University of Tromsø, Norway (S.K.B., J.- B.H.); Department of Clinical Epidemiology, Leiden University Medical Center, University of Leiden, The Netherlands (S.C.C.); Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands (R.T.G.); Department of Exercise and Health Sciences, University of Massachusetts, Boston (P.N.G.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.H.); Laboratory for Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark (A.G.H.); Department of Clinical Cancer Prevention and Cardiology, University of Texas MD Anderson Cancer Center, Houston (S.G.L.); Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (P.L.L., A.R.F.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.); Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC (L.W.M.); Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (K. Matsushita, Y.S.); Department of Public Health, Section for Epidemiology, Aarhus University, and Department of Cardiology, Aalborg University Hospital, Denmark (K.O.); Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Denmark (E.P.); Framingham Heart Study, Boston University School of Medicine, MA (M.P.); National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.); and Department of Hematology, Aalborg University Hospital, Denmark (M.T.S.).

PMID: 27831499
PMCID: PMC5201424
DOI: 10.1161/CIRCULATIONAHA.116.024507

Meta-Analysis

Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies

Bakhtawar K Mahmoodi et al. Circulation. 2017.

. 2017 Jan 3;135(1):7-16.

doi: 10.1161/CIRCULATIONAHA.116.024507. Epub 2016 Nov 9.

Authors

Affiliations

¹ From Department of Cardiology and Internal Medicine, Sint Antonius Hospital, Nieuwegein, The Netherlands (B.K.M., W.J.B., J.t.B.); Department of Haematology, University Medical Center Groningen, University of Groningen, The Netherlands (B.K.M., K. Meijer); Departments of Medicine and Pathology, University of Vermont, Burlington (M.C., N.A.Z.); Department of Hematology, Trondheim University Hospital, Norway (I.A.N., J.H.); Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.); K. G. Jebsen-Thrombosis Research and Expertise Center, Department of Clinical Medicine, University of Tromsø, Norway (S.K.B., J.- B.H.); Department of Clinical Epidemiology, Leiden University Medical Center, University of Leiden, The Netherlands (S.C.C.); Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands (R.T.G.); Department of Exercise and Health Sciences, University of Massachusetts, Boston (P.N.G.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.H.); Laboratory for Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark (A.G.H.); Department of Clinical Cancer Prevention and Cardiology, University of Texas MD Anderson Cancer Center, Houston (S.G.L.); Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (P.L.L., A.R.F.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.); Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC (L.W.M.); Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (K. Matsushita, Y.S.); Department of Public Health, Section for Epidemiology, Aarhus University, and Department of Cardiology, Aalborg University Hospital, Denmark (K.O.); Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Denmark (E.P.); Framingham Heart Study, Boston University School of Medicine, MA (M.P.); National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.); and Department of Hematology, Aalborg University Hospital, Denmark (M.T.S.). b.k.mahmoodi@umcg.nl.
² From Department of Cardiology and Internal Medicine, Sint Antonius Hospital, Nieuwegein, The Netherlands (B.K.M., W.J.B., J.t.B.); Department of Haematology, University Medical Center Groningen, University of Groningen, The Netherlands (B.K.M., K. Meijer); Departments of Medicine and Pathology, University of Vermont, Burlington (M.C., N.A.Z.); Department of Hematology, Trondheim University Hospital, Norway (I.A.N., J.H.); Department of Family and Preventive Medicine, University of California San Diego, La Jolla (M.A.A.); K. G. Jebsen-Thrombosis Research and Expertise Center, Department of Clinical Medicine, University of Tromsø, Norway (S.K.B., J.- B.H.); Department of Clinical Epidemiology, Leiden University Medical Center, University of Leiden, The Netherlands (S.C.C.); Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands (R.T.G.); Department of Exercise and Health Sciences, University of Massachusetts, Boston (P.N.G.); Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle (S.H.); Laboratory for Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark (A.G.H.); Department of Clinical Cancer Prevention and Cardiology, University of Texas MD Anderson Cancer Center, Houston (S.G.L.); Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (P.L.L., A.R.F.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.E.M.); Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC (L.W.M.); Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (K. Matsushita, Y.S.); Department of Public Health, Section for Epidemiology, Aarhus University, and Department of Cardiology, Aalborg University Hospital, Denmark (K.O.); Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Denmark (E.P.); Framingham Heart Study, Boston University School of Medicine, MA (M.P.); National Heart, Lung, and Blood Institute, Bethesda, MD (J.E.R.); and Department of Hematology, Aalborg University Hospital, Denmark (M.T.S.).

PMID: 27831499
PMCID: PMC5201424
DOI: 10.1161/CIRCULATIONAHA.116.024507

Erratum in

Correction to: Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies.
[No authors listed] [No authors listed] Circulation. 2017 Mar 21;135(12):e788. doi: 10.1161/CIR.0000000000000497. Circulation. 2017. PMID: 28320813 No abstract available.

Abstract

Background: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE).

Methods: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis.

Results: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively.

Conclusions: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE.

Keywords: cardiovascular disease; diabetes mellitus; hyperlipidemia; hypertension; risk factors; smoking; venous thromboembolism.

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Conflict of interest statement

Disclosures: None declared. All authors submitted the ICMJE form on Disclosure of Potential Conflicts of Interest. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Figures

**Figure 1. Flow diagram for selection of studies**

**Figure 2. Pooled and study-specific hazard ratios of overall VTE**
The top panel shows the pooled estimates from crude models (Model 1); age, sex and BMI adjusted models (Model 2); and fully adjusted models (Model 3). The fully adjusted model included age, sex, race, BMI (continuous), history of CVD, history of VTE, hypertension, hypercholesterolemia, diabetes, former and current smoking. The bottom panel shows study-specific hazard ratios of overall VTE for hypertension, hypercholesterolemia, diabetes, and current smoking adjusted for age, sex and BMI. VTE denotes venous thromboembolism; and Part., participants.

Figure 3. Pooled hazard ratios of overall VTE according to blood pressure measurements for systolic pressure (panel A), diastolic pressure (panel B), pulse pressure (Panel C) and mean arterial pressure (Panel D)
Estimates are adjusted for age, sex, BMI (continuous), history of cardiovascular disease and antihypertensive medication use. The black line and the error-bars depict hazard rations and 95% confidence interval with the red dots indicating statistical significance (P<0.05) and the black diamond the reference value. The heights of the bars shown with the gray lines at the bottom of each graph depict the number of participants at each spline section and the widths of these bars correspond to the splines range.

Figure 4. Pooled hazard ratios of overall VTE according to lipid measurements for total cholesterol (panel A), low-density lipoproteins (panel B), high-density lipoproteins (Panel C) and triglycerides (Panel D) levels
Estimates are adjusted for age, sex, BMI (continuous), history of cardiovascular disease and lipid-lowering medication use. The black line and the error-bars depict hazard rations and 95% confidence interval with the red dots indicating statistical significance (P<0.05) and the black diamond the reference value. The heights of the bars shown with the gray lines at the bottom of each graph depict the number of participants at each spline section and the widths of these bars correspond to the splines range.

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Comment in

Smoking: A Dual Pathogen for Arterial and Venous Thrombosis.
Anand SS. Anand SS. Circulation. 2017 Jan 3;135(1):17-20. doi: 10.1161/CIRCULATIONAHA.116.025024. Circulation. 2017. PMID: 28028060 No abstract available.

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References

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1. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M, Europe VTEIAGi. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98:756–64. - PubMed
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1. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4–8. - PubMed
1. Goff DC, Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Sr, Gibbons R, Greenland P, Lackland DT, Levy D, O'Donnell CJ, Robinson J, Schwartz JS, Shero ST, Smith SC, Jr, Sorlie P, Stone NJ, Wilson PW. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129:S49–73. - PubMed

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[1] Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38:S495–501. - PubMed

[2] Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38:S495–501. - PubMed

[3] Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M, Europe VTEIAGi. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98:756–64. - PubMed

[4] Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier D, Oger E, Samama MM, Spannagl M, Europe VTEIAGi. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98:756–64. - PubMed

[5] Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost. 1999;82:610–9. - PubMed

[6] Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost. 1999;82:610–9. - PubMed

[7] White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4–8. - PubMed

[8] White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4–8. - PubMed

[9] Goff DC, Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Sr, Gibbons R, Greenland P, Lackland DT, Levy D, O'Donnell CJ, Robinson J, Schwartz JS, Shero ST, Smith SC, Jr, Sorlie P, Stone NJ, Wilson PW. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129:S49–73. - PubMed

[10] Goff DC, Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Sr, Gibbons R, Greenland P, Lackland DT, Levy D, O'Donnell CJ, Robinson J, Schwartz JS, Shero ST, Smith SC, Jr, Sorlie P, Stone NJ, Wilson PW. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129:S49–73. - PubMed

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Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies

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Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies

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