Small-Area Analysis of Treatment and Clinical Outcomes in Patients with Venous Thromboembolism in Denmark: A Nationwide Cohort Study

Abstract

Objectives To investigate geographical variation in initiation and extended treatment with anticoagulants and clinical outcomes among patients hospitalized with first-time venous thromboembolism (VTE) in Denmark between 2007 and 2018.

Methods Using nationwide health care registries, we identified all patients with a first-time VTE hospital diagnosis supported by imaging data from 2007 to 2018. Patients were grouped according to residential region (5) and municipality (98) at the time of VTE diagnosis. Cumulative incidence of initiation of and extended (beyond 365 days) anticoagulation treatment as well as clinical outcomes, including recurrent VTE, major bleeding, and all-cause death, were assessed. Sex- and age-adjusted relative risks (RRs) of the outcomes were computed when comparing across individual regions and municipalities. Overall geographic variation was quantified by computing the median RR.

Results We identified 66,840 patients with a first-time VTE hospitalization. A difference in initiation of anticoagulation treatment of more than 20 percentage points between regions was observed (range: 51.9–72.4%, median RR: 1.09, 95% confidence interval [CI]: 1.04–1.13). Variation was also observed for extended treatment (range: 34.2–46.9%, median RR: 1.08, 95% CI: 1.02–1.14). The cumulative incidence of recurrent VTE ranged from 3.6 to 5.3% at 1 year (median RR: 1.08, 95% CI: 1.01–1.15). The difference remained after 5 years, and variation was also observed for major bleeding (median RR: 1.09, 95% CI: 1.03–1.15), whereas it appeared smaller for all-cause mortality (median RR: 1.03, 95% CI: 1.01–1.05).

Conclusion Substantial geographical variation in anticoagulation treatment and clinical outcomes occurs in Denmark. These findings indicate a need for initiatives to ensure uniform high-quality care for all VTE patients.

Keywords

venous thromboembolism - anticoagulation treatment - bleeding - death - small-area analysis

• References

• 1 Barco S, Mahmoudpour SH, Valerio L. et al. Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database. Lancet Respir Med 2020; 8 (03) 277-287
• 2 Kahn SR, Shrier I, Julian JA. et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149 (10) 698-707
• 3 Ende-Verhaar YM, Cannegieter SC, Vonk Noordegraaf A. et al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Respir J 2017; 49 (02) 1601792
• 4 Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012; 379 (9828): 1835-1846
• 5 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
• 6 Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. Clinical guideline. Published: June 27, 2012. nice.org.uk/guidance/cg144. Accessed April 13, 2023 at: https://www.nice.org.uk/guidance/cg144/resources/venous-thromboembolic-diseases-diagnosis-management-and-thrombophilia-testing-pdf-35109570835141
• 7 Grove EL, Schultz J, Kjærgaard J, Würtz M, Kümler T. Danish Society of Cardiology's national clinical guideline 2021. Chapter 12: Pulmonary embolism and deep vein thrombosis. Danish. Accessed April 13, 2023 at: nbv.cardio.dk/lungeemboli
• 8 Wennberg J, McPherson K, Goodman D. Small area analysis and the challenge of practice variation. In: Johnson A, Stukel T. eds. Medical Practice Variations. Boston, MA: Springer US; 2016: 1-25
• 9 Zakai NA, McClure LA, Judd SE. et al. Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. Circulation 2014; 129 (14) 1502-1509
• 10 Assareh H, Chen J, Ou L, Hillman K, Flabouris A. Incidences and variations of hospital acquired venous thromboembolism in Australian hospitals: a population-based study. BMC Health Serv Res 2016; 16 (01) 511
• 11 Douce D, McClure LA, Lutsey P, Cushman M, Zakai NA. Outpatient treatment of deep vein thrombosis in the United States: the reasons for geographic and racial differences in stroke study. J Hosp Med 2017; 12 (10) 826-830
• 12 Healthcare in Denmark - an overview [Internet]. Copenhagen 2017 [cited October 19, 2017]. 73 p. Accessed April 13, 2023 at: https://www.healthcaredenmark.dk/media/ykedbhsl/healthcare-dk.pdf
• 13 Mainz J, Hess MH, Johnsen SP. The Danish unique personal identifier and the Danish Civil Registration System as a tool for research and quality improvement. Int J Qual Health Care 2019; 31 (09) 717-720
• 14 Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol 2015; 7: 449-490
• 15 Kildemoes HW, Sørensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health 2011; 39 (7, Suppl): 38-41
• 16 Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol 2010; 63 (02) 223-228
• 17 Khan F, Rahman A, Carrier M. et al; MARVELOUS Collaborators. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ 2019; 366: l4363
• 18 Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014; 123 (12) 1794-1801
• 19 Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horváth-Puhó E, Sørensen HT. Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study. J Thromb Haemost 2014; 12 (08) 1207-1215
• 20 Overgaard M, Andersen PK, Parner ET. Regression analysis of censored data using pseudo-observations: an update. Stata J 2015; 15: 809-821
• 21 Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time. Stat Med 2007; 26 (24) 4505-4519
• 22 Parner ET, Andersen PK. Regression analysis of censored data using pseudo-observations. Stata J 2010; 10: 408-422
• 23 Aalen OO, Johansen S. An empirical transition matrix for nonhomogeneous Markov chains based on censored observations. Scand J Stat 1978; 5: 141-150
• 24 Henriksen DP, Rasmussen L, Hansen MR, Hallas J, Pottegård A. Comparison of the five Danish regions regarding demographic characteristics, healthcare utilization, and medication use–a descriptive cross-sectional study. PLoS One 2015; 10 (10) e0140197
• 25 Christesen AMS, Vinter N, Mortensen LS, Fenger-Grøn M, Johnsen SP, Frost L. Inequality in oral anticoagulation use and clinical outcomes in atrial fibrillation: a Danish nationwide perspective. Eur Heart J Qual Care Clin Outcomes 2018; 4 (03) 189-199
• 26 Johnsen SP, Rasmussen TB, Falstie-Jensen AM. et al. Effectiveness and safety of oral anticoagulation treatment beyond 1 year after venous thromboembolism in patients at intermediate recurrence risk. Basic Clin Pharmacol Toxicol 2021; 129 (03) 210-220
• 27 Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of actue venous thromboembolism: the Worcester venous thromboembolism study (1985 to 2009). Am J Med 2014; 127: 829-839
• 28 Arshad N, Isaksen T, Hansen J-B, Brækkan SK. Time trends in incidence rates of venous thromboembolism in a large cohort recruited from the general population. Eur J Epidemiol 2017; 32 (04) 299-305
• 29 Münster AM, Rasmussen TB, Falstie-Jensen AM. et al. A changing landscape: temporal trends in incidence and characteristics of patients hospitalized with venous thromboembolism 2006-2015. Thromb Res 2019; 176: 46-53
• 30 Gustafsson N, Poulsen PB, Stallknecht SE, Dybro L, Paaske Johnsen S. Societal costs of venous thromboembolism and subsequent major bleeding events: a national register-based study. Eur Heart J Qual Care Clin Outcomes 2020; 6 (02) 130-137
• 31 Albertsen IE, Goldhaber SZ, Piazza G. et al. Predictors of not initiating anticoagulation after incident venous thromboembolism: a Danish nationwide cohort study. Am J Med 2020; 133 (04) 463-472.e5
• 32 Flojstrup M, Bogh SBB, Bech M, Henriksen DP, Johnsen SP, Brabrand M. Mortality before and after reconfiguration of the Danish hospital-based emergency healthcare system: a nationwide interrupted time series analysis. BMJ Qual Saf 2023; 32 (04) 202-213