Clinical Research in Cardiology

, Volume 108, Issue 1, pp 101–109 | Cite as

Sex differences in risk of incident venous thromboembolism in heart failure patients

  • Line MelgaardEmail author
  • Peter Brønnum Nielsen
  • Thure Filskov Overvad
  • Flemming Skjøth
  • Gregory Y. H. Lip
  • Torben Bjerregaard Larsen
Original Paper



In patients with incident heart failure, the risk of venous thromboembolism (VTE), defined as pulmonary embolism (PE) and/or deep venous thrombosis (DVT), is sparsely described, especially potential sex differences. We conducted an observational study to evaluate risk of VTE among male and female heart failure patients.


Population-based cohort study of patients diagnosed with incident heart failure during 2000–2015, identified by record linkage between nationwide registries in Denmark. Using a pseudo-value approach, we calculated relative risks [RR] of VTE at 1 and 3 years of follow-up. Crude VTE risk for males and females are reported and contrasted after adjustment for established clinical risk factors for VTE.


A total of 32,330 heart failure patients were included, of which 15,238 (47%) were females. For the combined endpoint of VTE, female sex was associated with a higher risk (1-year adjusted RR: 1.30, 95% confidence interval [CI]: 0.97–1.73; 3-year adjusted RR: 1.34, 95% CI: 1.07–1.67) compared to male patients. For the individual endpoints of PE and DVT after 1-year of follow-up, female sex was only associated with a higher risk of PE and not DVT, compared to male patients. However, female sex was associated with a higher risk of both PE and DVT after 3 years of follow-up.


Among incident heart failure patients, female sex is associated with a higher risk of VTE, mainly driven by an excess risk of PE. This finding may help improve clinical decision-making regarding VTE prophylaxis in patients with heart failure.


Heart failure Sex Venous thromboembolism Deep vein thrombosis Pulmonary embolism 



Confidence interval


Deep vein thrombosis


Heart failure


Pulmonary embolism


Relative risk


Venous thromboembolism



Line Melgaard, Peter Brønnum Nielsen, and Flemming Skjøth had full access to all of the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the design, analysis, interpretation of data, drafting the article, or revising it critically for important intellectual content and approved the final version to be published. Statistics Denmark provided the data for this study.


The Obel Family Foundation.

Compliance with ethical standards

Conflict of interest

Professor Lip: Consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally. Associate Professor Larsen: An investigator for Janssen Scientific Affairs, LLC, and Boehringer Ingelheim. Speaker for Bayer, BMS/Pfizer, Janssen Pharmaceuticals, Takeda, Roche Diagnostics, and Boehringer Ingelheim. Peter Brønnum Nielsen: Speaker for Boehringer Ingelheim and Bayer Pharma AG; research Grant from BMS/Pfizer. Flemming Skjøth: Consultancy fees from Bayer. Other authors—none declared. Profs Lip and Larsen are guarantors of this paper.

Supplementary material

392_2018_1329_MOESM1_ESM.pdf (87 kb)
Supplementary material 1 (PDF 87 KB)


  1. 1.
    Haeusler KG, Laufs U, Endres M (2011) Chronic heart failure and ischemic stroke. Stroke 42:2977–2982CrossRefGoogle Scholar
  2. 2.
    Shantsila E, Lip GYH (2014) Thrombotic complications in heart failure: an underappreciated challenge. Circulation 130:387–389CrossRefGoogle Scholar
  3. 3.
    Patel K, Fasanya A, Yadam S, Joshi AA, Singh AC, DuMont T (2017) Pathogenesis and epidemiology of venous thromboembolic disease. Crit Care Nurs Q 40:191–200CrossRefGoogle Scholar
  4. 4.
    Edelsberg J, Hagiwara M, Taneja C, Oster G (2006) Risk of venous thromboembolism among hospitalized medically ill patients. Am J Heal Pharm 63:S16–S22CrossRefGoogle Scholar
  5. 5.
    Spyropoulos AC, Hussein M, Lin J, Battleman D (2009) Rates of venous thromboembolism occurrence in medical patients among the insured population. Thromb Haemost 102:951–957CrossRefGoogle Scholar
  6. 6.
    Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR et al. (2008) Prevention of venous thromboembolism: American College of chest physicians evidence-based clinical practice guidelines (8th edn). Chest 133:381S–453SCrossRefGoogle Scholar
  7. 7.
    Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM et al (2010) HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 16:e1–e194CrossRefGoogle Scholar
  8. 8.
    Mebazaa A, Spiro TE, Büller HR, Haskell L, Hu D, Hull R et al (2014) Predicting the risk of venous thromboembolism in patients hospitalized with heart failure. Circulation 130:410–418CrossRefGoogle Scholar
  9. 9.
    Dries D, Rosenberg Y, Waclawiw M, Domanski M (1997) Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol 29:1074–1080CrossRefGoogle Scholar
  10. 10.
    Beemath A, Stein PD, Skaf E, Al Sibae MR, Alesh I (2006) Risk of venous thromboembolism in patients hospitalized with heart failure. Am J Cardiol 98:793–795CrossRefGoogle Scholar
  11. 11.
    Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158:585–593CrossRefGoogle Scholar
  12. 12.
    Bauersachs RM, Riess H, Hach-Wunderle V, Gerlach H, Carnarius H, Eberle S et al (2010) Impact of gender on the clinical presentation and diagnosis of deep-vein thrombosis. Thromb Haemost 103:710–717CrossRefGoogle Scholar
  13. 13.
    Roseann Andreou E, Koru-Sengul T, Linkins L, Bates SM, Ginsberg JS, Kearon C (2008) Differences in clinical presentation of deep vein thrombosis in men and women. J Thromb Haemost 6:1713–1719CrossRefGoogle Scholar
  14. 14.
    Pedersen CB (2011) The danish civil registration system. Scand J Public Health 39(7 Suppl):22–25CrossRefGoogle Scholar
  15. 15.
    Lynge E, Sandegaard JL, Rebolj M (2011) The Danish National Patient Register. Scand J Public Health 39(7 Suppl):30–33CrossRefGoogle Scholar
  16. 16.
    Kildemoes HW, Sørensen HT, Hallas J (2011) The Danish National Prescription Registry. Scand J Public Health 39(7 Suppl):38–41CrossRefGoogle Scholar
  17. 17.
    Kümler T, Gislason GH, Kirk V, Bay M, Nielsen OW, Køber L et al (2008) Accuracy of a heart failure diagnosis in administrative registers. Eur J Heart Fail 10:658–660CrossRefGoogle Scholar
  18. 18.
    Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sørensen HT (2011) The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol 11:83CrossRefGoogle Scholar
  19. 19.
    Sundbøll J, Adelborg K, Munch T, Frøslev T, Toft Sørensen H, Erik Bøtker H et al. (2016) Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study. BMJ Open 6:e012832CrossRefGoogle Scholar
  20. 20.
    Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horváth-Puhó E, Sørensen HT (2014) Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study. J Thromb Haemost 12:1207–1215CrossRefGoogle Scholar
  21. 21.
    Delekta J, Hansen SM, AlZuhairi KS, Bork CS, Joensen AM (2018) The validity of the diagnosis of heart failure (I50.0–I50.9) in the Danish National Patient Register. Dan Med J 65:2–6Google Scholar
  22. 22.
    Zöller B, Ji J, Sundquist J, Sundquist K (2012) Risk of haemorrhagic and ischaemic stroke in patients with cancer: a nationwide follow-up study from Sweden. Eur J Cancer 48:1875–1883CrossRefGoogle Scholar
  23. 23.
    Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP (2010) Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol 63:223–228CrossRefGoogle Scholar
  24. 24.
    Gooley T, Leisenring W, Crowley J, Storer B (1999) Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 18:695–706CrossRefGoogle Scholar
  25. 25.
    Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N et al (2014) 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 35:3033–3080CrossRefGoogle Scholar
  26. 26.
    Mahmoodi BK, Cushman M, Næss IA, Allison MA, Bos WJ, Brækkan SK et al (2017) Association of traditional cardiovascular risk factors with venous thromboembolism. Circulation 135:7–16CrossRefGoogle Scholar
  27. 27.
    Cole SR, Hernán MA (2004) Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed 75:45–49CrossRefGoogle Scholar
  28. 28.
    Klein J, Andersen P (2005) Regression modeling of competing risks data based on pseudovalues of the cumulative incidence function. Biometrics 61:223–229CrossRefGoogle Scholar
  29. 29.
    Klein J, Logan B, Harhoff M, Andersen P (2007) Analyzing survival curves at a fixed point in time. Stat Med 26:4505–4519CrossRefGoogle Scholar
  30. 30.
    Glynn RJ, Schneeweiss S, Stürmer T (2006) Indications for propensity scores and review of their use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 98:253–259CrossRefGoogle Scholar
  31. 31.
    Haskins IN, Amdur R, Sarani B, Vaziri K (2015) Congestive heart failure is a risk factor for venous thromboembolism in bariatric surgery. Surg Obes Relat Dis 11:1140–1145CrossRefGoogle Scholar
  32. 32.
    Severinsen MT, Johnsen SP, Tjønneland A, Overvad K, Dethlefsen C, Kristensen SR (2010) Body height and sex-related differences in incidence of venous thromboembolism: a Danish follow-up study. Eur J Intern Med 21:268–272CrossRefGoogle Scholar
  33. 33.
    Dean SM, Abraham W (2010) Venous thromboembolic disease in congestive heart failure. Congest Hear Fail 16:164–169CrossRefGoogle Scholar
  34. 34.
    Howell MD, Geraci JM, Knowlton AA (2001) Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 54:810–816CrossRefGoogle Scholar
  35. 35.
    Rothberg MB, Lindenauer PK, Lahti M, Pekow PS, Selker HP (2011) Risk factor model to predict venous thromboembolism in hospitalized medical patients. J Hosp Med 6:202–209CrossRefGoogle Scholar
  36. 36.
    Stein PD, Hull RD, Kayali F, Ghali WA, Alshab AK, Olson RE (2004) Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med 164:2260–2265CrossRefGoogle Scholar
  37. 37.
    Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ (2005) Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 143:697–706CrossRefGoogle Scholar
  38. 38.
    Gomes MPV, Deitcher SR (2004) Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review. Arch Intern Med 164:1965–1976CrossRefGoogle Scholar
  39. 39.
    van Heerebeek L, Paulus WJ (2016) Understanding heart failure with preserved ejection fraction: where are we today? Netherlands Hear J 24:227–236CrossRefGoogle Scholar
  40. 40.
    Andersson C, Vasan RS (2014) Epidemiology of heart failure with preserved ejection fraction. Hear Fail Clin 10:377–388CrossRefGoogle Scholar
  41. 41.
    Meyer S, Teerlink JR, Metra M, Ponikowski P, Cotter G, Davison BA et al (2017) Sex differences in early dyspnea relief between men and women hospitalized for acute heart failure: insights from the RELAX-AHF study. Clin Res Cardiol 106:280–292CrossRefGoogle Scholar
  42. 42.
    Rizkallah J, Man SFP, Sin DD (2009) Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis. Chest 135:786–793CrossRefGoogle Scholar
  43. 43.
    Jois-Bilowich P, Michota F, Bartholomew JR, Glauser J, Diercks D, Weber J et al (2008) Venous thromboembolism prophylaxis in hospitalized heart failure patients. J Card Fail 14:127–132CrossRefGoogle Scholar
  44. 44.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH et al (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62:e147–e239CrossRefGoogle Scholar
  45. 45.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 37:2129–2200CrossRefGoogle Scholar
  46. 46.
    Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A et al (2016) Extended thromboprophylaxis with betrixaban in acutely Ill medical patients. N Engl J Med 375:534–544CrossRefGoogle Scholar
  47. 47.
    Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P et al (2010) Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 153:8–18CrossRefGoogle Scholar
  48. 48.
    Albertsen IE, Larsen TB, Rasmussen LH, Overvad TF, Lip GY (2012) Prevention of venous thromboembolism with new oral anticoagulants versus standard pharmacological treatment in acute medically ill patients. A systematic review and meta-analysis. Drugs 72:1755–1764CrossRefGoogle Scholar
  49. 49.
    Raskob GE, Spyropoulos AC, Zrubek J, Ageno W, Albers G, Elliott G et al (2016) The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost 115:1240–1248CrossRefGoogle Scholar
  50. 50.
    Mard S, Nielsen FE (2010) Positive predictive value and impact of misdiagnosis of a heart failure diagnosis in administrative registers among patients admitted to a University Hospital cardiac care unit. Clin Epidemiol 2:235–239Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Line Melgaard
    • 1
    • 2
    Email author
  • Peter Brønnum Nielsen
    • 1
    • 2
  • Thure Filskov Overvad
    • 1
    • 2
  • Flemming Skjøth
    • 1
    • 2
  • Gregory Y. H. Lip
    • 1
    • 4
  • Torben Bjerregaard Larsen
    • 1
    • 2
    • 3
  1. 1.Center of Thrombosis and Drug Research, Department of CardiologyAalborg University HospitalAalborgDenmark
  2. 2.Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of HealthAalborg UniversityAalborgDenmark
  3. 3.Department of CardiologyAalborg University HospitalAalborgDenmark
  4. 4.Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK

Personalised recommendations