Abstract
Aims
Patients with congenital heart disease (CHD) have an increased risk of developing acquired cardiovascular diseases. However, the risk of venous thromboembolism (VTE) in patients with CHD is unknown. We aimed to investigate the incidence and risk of VTE in patients with CHD compared with matched controls without CHD.
Methods and results
Data from Swedish health registers were used to identify all patients with CHD between 1970 and 2017 in Sweden. Each patient with CHD was matched with 10 controls from the Swedish Total Population Register. The primary outcome of the study was an event of VTE. Follow-up was from birth until VTE, death, or the end of the study (2017). Cox proportional hazard models were used to investigate the risk of VTE in patients with CHD and controls. A total of 67 814 patients with CHD and 583 709 matched controls were identified and included in the study. During a mean follow-up of 15.9 (SD ± 12.5) years, 554 (0.8%) patients with CHD and 1571 (0.3%) controls developed VTE. The risk of VTE was 3.3 [95% confidence interval [CI] 2.6–3.4) times higher in patients with CHD than in controls. Patients with conotruncal defects had the highest risk of VTE (hazard ratio 7.06, 95% CI 5.52–9.03).
Conclusion
In our nationwide study, we found that the risk of VTE in patients with CHD was more than three times higher than in matched controls. The highest risk of VTE was in patients with the most complex lesions. Further research is crucial to clarify the underlying risk factors and prevent VTE in patients with CHD.
Keywords: Congenital heart disease, Venous thromboembolism, Register based, Nationwide study
Structured Graphical abstract
Graphical Abstract.
Introduction
Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is the third most common vascular disease globally1 with an incidence of 100–200 cases per 100 000 person-years.2–7 The risk of VTE increases with age.2,4,7 The survival of patients with congenital heart disease (CHD) has increased exponentially between 1980 and 2000. Currently, 97% of patients with CHD survive to adult age, although the risk of mortality is still significantly higher in patients with CHD than in the general population.8 As patients with CHD age, the risk of conditions related to increased age and acquired risk factors,9 such as diabetes mellitus10 or hypertension, also increases. However, because of their condition, patients with CHD already have an increased risk of several medical conditions such as atrial fibrillation,11 ischaemic stroke,12,13 heart failure,14,15 and ischaemic heart disease,16 in comparison with matched controls. The risk of VTE in patients with CHD in Sweden is unknown, with no previous studies available. The aim of the present study was to determine the incidence rate and risk of VTE in patients with CHD compared with matched controls that do not have CHD in Sweden. An additional aim was to determine if the risk of VTE varies depending on the type of CHD lesion.
Methods
Study population and data collection procedures
We used data from the Swedish National Patient Register to identify all patients born in Sweden between 1 January 1970 and 31 December 2017 with a diagnosis of CHD. Ten controls from the Total Population Register in Sweden were randomly assigned to each included patient with CHD and matched by sex and year of birth. The exclusion criteria were country of birth other than Sweden and year of birth between 1930 and1969. The number of controls was chosen to cover an eventual loss of controls owing to the exclusion criteria, moving abroad from Sweden, or other factors that would make follow-up impossible. Because of a potential loss of controls, the ratio between the patients with CHD and controls included in this study might not be 1 to 10. Patients with a diagnosis of CHD after VTE event were not included in the study. Patients with CHD and controls were followed up through the Swedish National Patient Register and the National Cause of Death Register. The Swedish National Patient Register includes data since 1987 for inpatient care and also data from 2001 for outpatient care. The study population has been included and described in earlier studies.11,12,16,17
Definitions
Congenital heart disease and VTE were defined as receiving a corresponding diagnosis according to the International Statistical Classification of Disease and Related Health Problems (ICD) (see Supplementary material online, Tables S1 and S2). Venous thromboembolism is an umbrella term that includes PE, DVT, and thromboembolic event in other veins of the human body. In this study, the events were divided into PE (embolus in the lung), DVT (thrombosis in the deep veins), and other thromboembolic event (thromboembolic event in the remaining veins). The ICD Eighth, Ninth (Swedish version), and Tenth Revisions were used. Patients were divided into six groups according to the hierarchic lesion categorization proposed by Botto et al.18 and modified by Liu et al.19 This categorization has been used and described in earlier studies.11,16,20,21 The six groups were following: conotruncal defects, non-conotruncal defects, coarctation of the aorta, ventricular septal defect (VSD), atrial septal defect (ASD), and other lesions. Because of a low number of events, the groups were classified into complex lesions and non-complex lesions. The complex lesion group comprised patients with conotruncal and non-conotruncal defects, and the non-complex lesion group included the remaining four groups.
Statistics
R Studio software (version 4.2.0)22 was used for the statistical analyses (The R Project for Statistical Computing, Vienna, Austria). Continuous data are presented as mean and standard deviation (SD) and categorical data as frequency and percentage. For continuous data, the t-test was used to compare differences in mean values and the χ2 test for categorical data. A P < 0.05 was recognized as statistically significant. In the current study, all patients with CHD and matched controls were followed from birth until the first event of VTE, death, or the end of the study (31 December 2017), whichever occurred first. The incidence rate per 10 000 person-years was estimated as the total number of events divided by the total follow-up time (in years). Because of the long follow-up period, cumulative incidence curves were estimated with competing risk according to the Fine–Grey method, with 95% confidence intervals (CIs). Hazard ratios (HRs) with 95% CIs were estimated using a Cox regression model to compare the risk of VTE between CHD and controls (reference group). All models were adjusted for sex, year of birth, and baseline comorbidities (defined as before an event of VTE). A sensitivity analysis was conducted to examine how surgery affected the frequency of VTE events.
Ethics
The project has been approved by the Regional Research Ethics Board in Gothenburg (Gbg 912-16, T619-18). The data used in this study were pseudonymized; therefore, an exception was made regarding informed consent for participation in medical research.
Results
A total of 67 814 individuals with CHD and 583 709 matched controls were identified. Of these, 34 173 (50.4%) and 294 146 (50.4%) were men, respectively. Table 1 shows the characteristics of the study populations. During a mean follow-up time of 15.9 (SD ± 12.5) years, 554 (0.8%) patients with CHD and 1571 (0.3%) controls developed VTE; of these, 241 (0.4%) patients with CHD and 1045 (0.2%) controls developed DVT and 162 (0.2%) patients with CHD and 452 (0.1%) controls developed PE.
Table 1.
Characteristics of the study population
| Characteristic | Patients with CHD (n = 67 814), n (%) | Controls (n = 583 709), n (%) | P value |
|---|---|---|---|
| Sex | 1.000 | ||
| Male | 34 173 (50.4%) | 294 146 (50.4%) | |
| Female | 33 641 (49.6%) | 289 563 (49.6%) | |
| Year of birth | 1999.6 ± 12.8 | 2000.6 ± 12.6 | <0.001 |
| Birth period | <0.001 | ||
| 1970–1979 | 6760 (10.0%) | 51 843 (8.9%) | |
| 1980–1989 | 8933 (13.2%) | 65 254 (11.2%) | |
| 1990–1999 | 13 054 (19.2%) | 109 864 (18.8%) | |
| 2000–2009 | 20 372 (30.0%) | 180 630 (30.9%) | |
| 2010–2017 | 18 695 (27.6%) | 176 118 (30.2%) | |
| Classification 1 | |||
| Lesion group 1 | 4969 (7.3%) | 42 379 (7.3%) | |
| Lesion group 2 | 3671 (5.4%) | 29 714 (5.1%) | |
| Lesion group 3 | 3183 (4.7%) | 26 318 (4.5%) | |
| Lesion group 4 | 22 072 (32.5%) | 191 542 (32.8%) | |
| Lesion group 5 | 13 730 (20.2%) | 121 941 (20.9%) | |
| Lesion group 6 | 20 189 (29.8%) | 171 815 (29.4%) | |
| Classification 2 | |||
| Complex lesion | 8640 (12.7%) | 72 093 (12.4%) | |
| Non-complex lesion | 59 174 (87.3%) | 511 616 (87.6%) | |
| Follow-up time | 15.9 ± 12.5 | 16.9 ± 12.5 | <0.001 |
| VTE event | 554 (0.8%) | 1571 (0.3%) | <0.001 |
| DVT event | 241 (0.4%) | 1045 (0.2%) | <0.001 |
| PE event | 162 (0.2%) | 452 (0.1%) | <0.001 |
| Other thromboembolic event | 234 (0.3%) | 348 (0.1%) | <0.001 |
Lesion group 1—conotruncal defects, lesion group 2—non-conotruncal defects, lesion group 3—coarctation of the aorta, lesion group 4—ventricular septal defect, lesion group 5—atrial septal defect, lesion group 6—other lesions. Complex lesions consist of Groups 1 and 2. Non-complex lesions consist of Groups 3–6. Controls did not have any congenital heart defects. Numbers in lesion groups in the control column show the number of matched controls in each lesion group. Year of birth and follow-up time in the table are presented as mean with SD.
CHD, congenital heart defects; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism.
Characteristics of the study population with CHD according to lesion group are shown in Table 2. The highest number of VTE events was found in lesion group 1 (101 events, 2.0%). Dividing VTE events into DVT, PE, and other thromboembolic event showed that all three types of thromboembolic events were more common in patients with CHD than in their controls (Table 3). The number of VTE events in patients with complex lesions was 160 (1.9%) and 394 in patients with non-complex lesions (0.7%). The percentage of events in the DVT, PE, and other thromboembolic event groups were higher in patients with complex lesions than in those with non-complex lesions. Deep vein thrombosis was diagnosed in 51 (0.6%) patients in the complex group and 190 (0.3%) in patients with non-complex lesions. For PE, the numbers were 46 (0.5%) and 116 (0.2%), respectively.
Table 2.
Characteristics of patients with congenital heart defects, according to lesion group
| Patients with CHD | |||||||
|---|---|---|---|---|---|---|---|
| Characteristic | Lesion group 1 | Lesion group 2 | Lesion group 3 | Lesion group 4 | Lesion group 5 | Lesion group 6 | P value |
| Sex | <0.001 | ||||||
| Male | 2953 (59.4%) | 1784 (48.6%) | 1917 (60.2%) | 10 480 (47.5%) | 6549 (47.7%) | 10 490 (52.0%) | |
| Female | 2016 (40.6%) | 1887 (51.4%) | 1266 (39.8%) | 11 592 (52.5%) | 7181 (52.3%) | 9699 (48.0%) | |
| Year of birth | 1995.0 ± 12.9 | 1992.9 ± 13.2 | 1995.0 ± 13.6 | 2003.1 ± 11.3 | 2002.8 ± 12.0 | 1996.6 ± 12.9 | <0.001 |
| Birth period | <0.001 | ||||||
| 1970–1979 | 752 (15.1%) | 726 (19.8%) | 544 (17.1%) | 1196 (5.4%) | 1018 (7.4%) | 2524 (12.5%) | |
| 1980–1989 | 990 (19.9%) | 784 (21.4%) | 599 (18.8%) | 1861 (8.4%) | 1060 (7.7%) | 3639 (18.0%) | |
| 1990–1999 | 1221 (24.6%) | 905 (24.7%) | 690 (21.7%) | 3220 (14.6%) | 1922 (14.0%) | 5096 (25.2%) | |
| 2000–2009 | 1180 (23.7%) | 770 (21.0%) | 760 (23.9%) | 8107 (36.7%) | 4816 (35.1%) | 4739 (23.5%) | |
| 2010–2017 | 826 (16.6%) | 486 (13.2%) | 590 (18.5%) | 7688 (34.8%) | 4914 (35.8%) | 4191 (20.8%) | |
| Follow-up time in years | 16.5 ± 13.2 | 13.9 ± 14.1 | 19.6 ± 13.9 | 13.9 ± 11.0 | 14.4 ± 11.9 | 18.8 ± 13.2 | <0.001 |
| VTE event | 101 (2.0%) | 59 (1.6%) | 25 (0.8%) | 86 (0.4%) | 102 (0.7%) | 181 (0.9%) | <0.001 |
Lesion group 1—conotruncal defects, lesion group 2—non-conotruncal defects, lesion group 3—coarctation of the aorta, lesion group 4—ventricular septal defect, lesion group 5—atrial septal defect, lesion group 6—other lesions. Year of birth and follow-up time in the table are presented as mean with SD.
CHD, congenital heart defects; VTE, venous thromboembolism; PE, pulmonary embolism.
Table 3.
Number of events of venous thromboembolism in patients with congenital heart defects and controls divided by lesion group
| Complex lesion | Non-complex lesion | |||||
|---|---|---|---|---|---|---|
| Patients with CHD, n (%) | Controls, n (%) | P value | Patients with CHD, n (%) | Controls, n (%) | P value | |
| VTE event | 160 (1.9) | 318 (0.4) | <0.001 | 394 (0.7) | 1253 (0.2) | <0.001 |
| DVT event | 51 (0.6) | 206 (0.3) | <0.001 | 190 (0.3) | 839 (0.2) | <0.001 |
| PE event | 46 (0.5) | 93 (0.1) | <0.001 | 116 (0.2) | 359 (0.1) | <0.001 |
| Other thromboembolic event | 86 (1.0) | 66 (0.1) | <0.001 | 148 (0.3) | 282 (0.1) | <0.001 |
Complex lesions consist of conotruncal and non-conotruncal defects. Non-complex lesions consist of coarctation of the aorta, ventricular septal defect, atrial septal defect, and other lesions. Other thrombosis event indicates thrombosis in veins other than the deep veins of the body or pulmonary embolism.
CHD, congenital heart defects; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism.
As shown in Table 4, the incidence of VTE per 10 000 patient-years at risk in patients with CHD was 5.13 (95% CI 4.71–5.57), compared with 1.59 (95% CI 1.51–1.67) in the control group. The incidence was higher in women than in men in both the CHD and control groups. In all lesion groups, the incidence of VTE was higher among individuals with CHD than that in their controls. The incidence was highest in patients from lesion group 1 with conotruncal defects. Generally, the incidence of a VTE event increased with older age.
Table 4.
Incidence of venous thromboembolism in patients with congenital heart disease and matched controls per 10 000 patient-years at risk
| Patients with CHD | Controls | |||||
|---|---|---|---|---|---|---|
| Patients with CHD, n (%) | VTE events, n (%) | Incidence rate of VTE (95% CI) | Controls, n (%) | VTE events, n (%) | Incidence rate of VTE (95% CI) | |
| All CHD | 67 814 (100) | 554 (0.82) | 5.13 (4.71–5.57) | 583 709 (100) | 1571 (0.27) | 1.59 (1.51–1.67) |
| Lesion group 1 | 4969 (7.3) | 101 (2.03) | 12.35 (10.06–15.01) | 42 379 (7.3) | 171 (0.40) | 1.91 (1.63–2.22) |
| Lesion group 2 | 3671 (5.4) | 59 (1.61) | 11.56 (8.80–14.91) | 29 714 (5.1) | 147 (0.49) | 2.14 (1.80–2.51) |
| Lesion group 3 | 3183 (4.7) | 25 (0.79) | 4.01 (2.59–5.92) | 26 318 (4.5) | 108 (0.41) | 1.95 (1.60–2.36) |
| Lesion group 4 | 22 072 (32.5) | 86 (0.39) | 2.80 (2.24–3.46) | 191 542 (32.8) | 341 (0.18) | 1.30 (1.17–1.45) |
| Lesion group 5 | 13 730 (20.2) | 102 (0.74) | 5.15 (4.20–6.26) | 121 941 (20.9) | 236 (0.19) | 1.36 (1.20–1.55) |
| Lesion group 6 | 20 189 (29.8) | 181 (0.90) | 4.76 (4.09–5.51) | 171 815 (29.4) | 568 (0.33) | 1.68 (1.54–1.82) |
| Complex lesion | 8640 (12.7) | 160 (1.85) | 12.05 (10.25–14.06) | 72 093 (12.4) | 318 (0.44) | 2.01 (1.79–2.24) |
| Non-complex lesion | 59 174 (87.3) | 394 (0.67) | 4.16 (3.76–4.59) | 511 616 (87.6) | 1253 (0.24) | 1.51 (1.43–1.60) |
| 1970–1979 | 6760 (10.0) | 199 (2.94) | 8.58 (7.43–9.86) | 51 843 (8.9) | 712 (1.37) | 3.24 (3.00–3.49) |
| 1980–1989 | 8933 (13.2) | 145 (1.62) | 5.96 (5.03–7.01) | 65 254 (11.2) | 471 (0.72) | 2.25 (2.05–2.46) |
| 1990–1999 | 13 054 (19.2) | 98 (0.75) | 3.56 (2.89–4.34) | 109 864 (18.8) | 310 (0.28) | 1.22 (1.09–1.36) |
| 2000–2009 | 20 372 (30.9) | 60 (0.29) | 2.38 (1.82–3.06) | 180 630 (30.9) | 44 (0.02) | 0.19 (0.14–0.26) |
| 2010–2017 | 18 695 (27.6) | 52 (0.28) | 6.70 (5.00–8.78) | 176 118 (30.2) | 34 (0.02) | 0.46 (0.32–0.64) |
| Women | 33 641 (49.6) | 295 (0.88) | 5.54 (4.93–6.21) | 289 563 (49.6) | 937 (0.32) | 1.92 (1.80–2.05) |
| Men | 34 173 (50.4) | 259 (0.76) | 4.73 (4.17–5.34) | 294 146 (50.4) | 634 (0.22) | 1.27 (1.17–1.37) |
Incidence rate is per 10 000 patient-years at risk. Lesion group 1—conotruncal defects, lesion group 2—non-conotruncal defects, lesion group 3—coarctation of the aorta, lesion group 4—ventricular septal defect, lesion group 5—atrial septal defect, lesion group 6—other lesions. Complex lesions consist of Groups 1 and 2. Non-complex lesions consist of Groups 3–6.
CHD, congenital heart defects; VTE, venous thromboembolism; CI, confidence interval.
Regardless of group, all patients with CHD had higher risk of VTE than their controls (Table 5). The risk was highest in lesion group 1 (conotruncal defects), lesion group 2 (non-conotruncal defects), and lesion group 5 (ASD): HR 7.06 (95% CI 5.52–9.03), 5.86 (95% CI 4.33–7.94), and 3.74 (95% CI 2.97–4.72), respectively. The highest risk of VTE was in patients with CHD born between 2010 and 2017, with HR 14.54 (95% CI 9.44–22.40). For all birth periods before 2000, the risk was not >2.94 compared with their controls.
Table 5.
Risk of venous thromboembolism in patients with congenital heart disease and matched controls
| VTE events in patients with CHD, n | VTE events in controls, n | HR (95% CI) | |
|---|---|---|---|
| All CHD | 554 | 1571 | 3.30 (2.99–6.63) |
| Lesion group 1 | 101 | 171 | 7.06 (5.52–9.03) |
| Lesion group 2 | 59 | 147 | 5.86 (4.33–7.94) |
| Lesion group 3 | 25 | 108 | 2.09 (1.35–3.23) |
| Lesion group 4 | 86 | 341 | 2.09 (1.65–2.65) |
| Lesion group 5 | 102 | 236 | 3.74 (2.97–4.72) |
| Lesion group 6 | 181 | 568 | 2.85 (2.41–3.36) |
| Complex lesion | 160 | 318 | 6.55 (5.42–7.93) |
| Non-complex lesion | 394 | 1253 | 2.74 (2.45–3.07) |
| 1970–1979 | 199 | 712 | 2.74 (2.34–3.21) |
| 1980–1989 | 145 | 471 | 2.68 (2.23–3.23) |
| 1990–1999 | 98 | 310 | 2.94 (2.35–3.69) |
| 2000–2009 | 60 | 44 | 12.38 (8.39–18.26) |
| 2010–2017 | 52 | 34 | 14.54 (9.44–22.40) |
| Women | 295 | 937 | 2.96 (2.59–3.37) |
| Men | 259 | 634 | 3.81 (3.29–4.40) |
Lesion group 1—conotruncal defects, lesion group 2—non-conotruncal defects, lesion group 3—coarctation of the aorta, lesion group 4—ventricular septal defect, lesion group 5—atrial septal defect, lesion group 6—other lesions. Complex lesions consist of Groups 1 and 2. Non-complex lesions consist of Groups 3–6.
VTE, venous thromboembolism; CHD, congenital heart defects; HR, hazard ratio; CI, confidence interval.
The cumulative incidence of VTE for patients with CHD and controls at age 0–47 years is shown in Figure 1. From an early age, patients with CHD showed a higher cumulative incidence of VTE than controls. The cumulative incidence increased most at ∼40 years of age for both patients with CHD and controls.
Figure 1.
Cumulative incidence of venous thromboembolism (%) in patients with congenital heart defects (red) and controls (black) at age 0–47 years. VTE, venous thromboembolism; CHD, congenital heart disease.
Table 6 lists comorbidities and history of surgery in the study populations before a VTE event. Overall, heart surgery 6 months before an event was more common than any of the comorbidities in patients with CHD (0.3%). The most common comorbidity in the control population was hypertension, with 28 cases (<0.01%).
Table 6.
Comorbidities and history of surgery
| Comorbidity or surgery | Patients with CHD, n (%) | Controls, n (%) | P value |
|---|---|---|---|
| Hypertension | 17 (<0.01%) | 28 (<0.01%) | <1.000 |
| Diabetes mellitus | 10 (<0.01%) | 23 (<0.01%) | 0.001 |
| Atrial fibrillation | 27 (<0.01%) | 4 (<0.01%) | <0.001 |
| Ischaemic stroke | 17 (<0.01%) | 5 (<0.01%) | <0.001 |
| Hyperlipidaemia | 6 (<0.01%) | 9 (<0.01%) | 0.001 |
| Heart surgery within 6 months | 177 (0.3%) | 2 (<0.01%) | <0.001 |
| Previous heart surgery | 15 012 (22.1%) | 110 (<0.01%) | <0.001 |
| Cancer | 28 (<0.01%) | 85 (<0.01%) | <0.001 |
Heart surgery within 6 months is defined as heart surgery 6 months prior to a venous thrombosis event. Previous heart surgery is defined as heart surgery prior to a venous thrombosis event.
CHD, congenital heart defect.
In a sensitivity analysis where all patients with prior thoracic surgery at any time before a VTE event were excluded, there were 26 (0.9%) VTE events in the complex lesion group and 315 (0.4%) events in their controls. In the non-complex lesion group, the number of events in cases and controls was 286 (0.6%) and 1244 (0.2%), respectively. The risk of VTE in patients with complex CHD lesions was HR 4.25 (95% CI 2.85–6.35) and HR 2.89 (95% CI 2.54–3.28) in patients with non-complex lesions.
Discussion
A main finding of the present study was that patients with CHD had a more than three times higher risk of developing a VTE compared with matched controls that did not have CHD. The highest risk was in the group with the most complex CHD lesions (conotruncal defects). As expected, the VTE incidence increased with age and was highest in the group born during 1970–1979. The most common comorbidity for patients with CHD was heart surgery.
In a national register study of DVT and PE in Sweden, the expected incidence of VTE in the Swedish population under 40 years of age was similar to the incidence for controls in this study. The incidence rate per 100 000 was 11.7 for PE and 18.2 for DVT in age group 30–39 years.2 That study also showed that cancer was the most frequent comorbidity in cases of VTE.2 Previous studies have shown that cancer is more common among individuals with CHD than in controls without CHD.23 It is important to understand how the prevalence of risk factors for VTE differs between patients with CHD and the control population so that conclusions can be drawn regarding the greatest risk factors for VTE in patients with CHD.
Patients with ASD in this study had the third highest incidence and risk of VTE, and this was higher than in groups with more severe lesions, such as coarctation of the aorta or VSD. This finding is important because ASD is the most common CHD among adults in Sweden.24 Individuals with CHD have a high risk of atrial fibrillation,11 which affects blood flow through the heart and can lead to the formation of thrombus. In a study on thrombotic events in children with cardiac pathology, 6 of 21 affected children had ASD.25 However, all these individuals also had other heart defects. According to the hierarchical classification used in this research, these children would have been categorized into a more severe lesion group than ASD.
Another interesting finding was that the risk of VTE was much higher in the youngest birth cohorts of patients with CHD, in comparison with their controls, with an HR of >12 and 14 in patients with CHD born during 2000–2009 and 2010–2017, respectively. The incidence of VTE increases with age, and the number of events in the control group for the birth periods 2000–2009 and 2010–2017 was low, as expected. However, the high HRs for these birth periods showed that children with CHD have a greater risk of developing VTE (compared with their controls) than adults according to our results. There may be an explanation for this, such as improved diagnostics with wider use of computed tomography. A register study from Canada showed that 96% of children with VTE had a condition associated with thromboembolism.26 Because 96% of children had a risk factor for VTE, the percentage of idiopathic events in children can be assumed to be low; therefore, it can be assumed that having a heart defect is a stronger risk factor for thromboembolism during childhood than in adulthood.
In the present study, women in both the CHD and control groups had a higher incidence of VTE than men. This finding is consistent with previous observations of VTE. The study population in the present research was young and of reproductive age. Venous thromboembolism is more common in women than in men.6,27 However, the incidence was higher in women with CHD than that in their controls, with a 2.96 times higher risk. For men with CHD, the risk was 3.81 times higher than that in their controls. A possible explanation for these findings might be that in the general population in young adulthood, men have a lower incidence of VTE than women.
In the CALF study, which included patients with Fontan circulation, 10 individuals reported DVT and 10 reported PE, out of the 159 patients in the study population,28 which is equal to 12.6%. Patients with Fontan circulation could be compared with our patients who had CHD with a complex lesion; our patients had a percentage of VTE events of 1.85%, which is below the percentage in the CALF study. A possible explanation for the different ages of the populations in the two studies could be that all patients included in the CALF study were over 18 years of age and the mean age was 30.6 years. In the present study, the mean age (based on calculations of the mean patient birth year) was ∼17.4 years. Because VTE is more common with older age, the age difference could explain the different percentage of VTE events in the two studies. Furthermore, patients in the CALF study were selected from among patients in specialized adult congenital heart centres, which could affect the patient sample.
A VTE event occurred in 177 patients with heart surgery prior to the event. Sensitivity analysis showed that patients with CHD who did not undergo surgery had a higher risk of VTE than their controls. The conclusion could be that surgery itself does not increase the risk of a VTE event in patients with CHD, but rather other factors are responsible for this increased risk.
The present study has several strengths, as well as some limitations. The study was conducted among a large population of patients with CHD and controls, but the data lack information about patients born outside Sweden, which means that the study does not reflect the entire Swedish population. The group of CHD is heterogenous and consists of around 1800 different diagnosis combinations according to the European classification. We have used the Botto system due to previous work by us and others. The limitation of our study is that detailed information from medical charts is lacking making further subdivisions into specific diagnosis less meaningful but have the strength of being population based and with a minimum of lost to follow-up over a long period of time. Because VTE becomes more common with age, the younger population in this study could have had an impact on the low number of events. It is likely that an older study population would have had a higher number of events and a higher absolute risk. Furthermore, a limitation is that the Outpatient Register only includes data from 2001 onwards and that the Inpatient Register did not cover the whole of Sweden until 1987 meaning that possible VTE diagnoses before 2001 respectively 1987 could have been missed and the real incidence of VTE and the risk could have been underestimated in this study. Beginning in 1970, data collection for the Inpatient Register went from a pilot project to an all-inclusive effort to cover the entire country in 1987. The present study lack data from primary health care that would probably not affect the number of PE as those patients are usually hospitalized, but the number of DVT events could have been underestimated. A limitation in a register-based study is that the data are not collected by the researchers and in different hospitals, which could lead to differences in diagnoses and usage of ICD codes. To circumvent this limitation, the definition of VTE in this study included thromboses of other and unspecified sites. Another limitation in register-based studies could be low coverage, but because there is a legal obligation to fill in the registers the data were collected from, we can assume that this is not the case in this study. In Sweden, hospital reimbursements are not driven by the ICD code. We cannot rule out registration bias completely, but external validation of the registry shows positive value of 85–95% and sensitivity above 90%.29 The possible anticoagulation therapy among the patients and controls was not studied, but the presence of this could have had impact on the results. Despite this limitation, the study findings showed that individuals with CHD are at greater risk of developing VTE compared with a control population.
Conclusions
In this nationwide, register-based cohort study, the absolute risk of developing VTE was low for both patients with CHD and controls; however, the relative risk was more than three times higher in patients with CHD than in matched controls. The highest incidence and risk of VTE were found among patients in the group with the most severe CHD lesions (conotruncal defects). However, further research on the risk factors is of great importance in patients with CHD for optimization of prophylaxis against VTE.
Lead author biography
Dagmara Cuszynska-Kruk received her MD in 2023 when she graduated from Sahlgrenska Academy, Gothenburg, Sweden. She is now undertaking the Foundation Program and in her spare time working on the topic of congenital heart disease and venous thromboembolism with a research group led by Zacharias Mandalenakis, MD, PhD, at the Department of Molecular and Clinical Medicine, Sahlgrenska Academy, Gothenburg, Sweden.
Supplementary Material
Acknowledgements
We thank Analisa Avila, MPH, ELS, of Edanz (www.edanz.com/ac) for editing a draft of this manuscript.
Contributor Information
Dagmara Cuszynska-Kruk, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden.
Maria Fedchenko, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden; Department of Medicine, Geriatrics and Emergency Medicine, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Kok Wai Giang, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden; Department of Medicine, Geriatrics and Emergency Medicine, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Mikael Dellborg, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden; Department of Medicine, Geriatrics and Emergency Medicine, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Peter Eriksson, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden; Department of Medicine, Geriatrics and Emergency Medicine, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; Adult Congenital Heart Unit, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Per-Olof Hansson, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden; Department of Medicine, Geriatrics and Emergency Medicine, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Zacharias Mandalenakis, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Diagnosvägen 11, SE-416 50 Gothenburg, Sweden; Department of Medicine, Geriatrics and Emergency Medicine, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; Adult Congenital Heart Unit, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Data availability
Data are available from the sources stated in the article on request to the data providers, fulfilling legal and regulatory requirements, and with permission from the Swedish Ethical Review Authority.
Supplementary material
Supplementary material is available at European Heart Journal Open online.
Ethical approval
The project has been approved by the Regional Research Ethics Board in Gothenburg (Gbg 912-16, T619-18).
Funding
The present study was supported by grants from the Swedish state under an agreement between the Swedish government and county councils, the ALF agreement (grant numbers 236611 and 917361), and the Swedish Research Council (grant number 2019-00193 SIMSAM). The funding sources had no role in the study design, data collection, analysis, or writing the manuscript.
References
- 1. Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016;388:3060–3073. [DOI] [PubMed] [Google Scholar]
- 2. Glise Sandblad K, Rosengren A, Sörbo J, Jern S, Hansson P-O. Pulmonary embolism and deep vein thrombosis—comorbidities and temporary provoking factors in a register-based study of 1.48 million people. Res Pract Thromb Haemost 2022;6:e12714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015;12:464–474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Johnson SA, Eleazer GP, Rondina MT. Pathogenesis, diagnosis, and treatment of venous thromboembolism in older adults. J Am Geriatr Soc 2016;64:1869–1878. [DOI] [PubMed] [Google Scholar]
- 5. Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021;398:64–77. [DOI] [PubMed] [Google Scholar]
- 6. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585–593. [DOI] [PubMed] [Google Scholar]
- 7. Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 2006;21:722–727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Mandalenakis Z, Giang KW, Eriksson P, Liden H, Synnergren M, Wåhlander H, Fedchenko M, Rosengren A, Dellborg M. Survival in children with congenital heart disease: have we reached a peak at 97%? J Am Heart Assoc 2020;9:e017704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Mandalenakis Z, Skoglund K, Dellborg M. Congenital heart disease: the children will become elderly. Aging (Albany NY) 2019;11:851–852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Dellborg M, Björk A, Pirouzi Fard MN, Ambring A, Eriksson P, Svensson AM, Gudbjörnsdottir S. High mortality and morbidity among adults with congenital heart disease and type 2 diabetes. Scand Cardiovasc J 2015;49:344–350. [DOI] [PubMed] [Google Scholar]
- 11. Mandalenakis Z, Rosengren A, Lappas G, Eriksson P, Gilljam T, Hansson PO, Skoglund K, Fedchenko M, Dellborg M. Atrial fibrillation burden in young patients with congenital heart disease. Circulation 2018;137:928–937. [DOI] [PubMed] [Google Scholar]
- 12. Mandalenakis Z, Rosengren A, Lappas G, Eriksson P, Hansson PO, Dellborg M. Ischemic stroke in children and young adults with congenital heart disease. J Am Heart Assoc 2016;5:e003071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Lui GK, Saidi A, Bhatt AB, Burchill LJ, Deen JF, Earing MG, Gewitz M, Ginns J, Kay JD, Kim YY, Kovacs AH, Krieger EV, Wu FM, Yoo S-J; American Heart Association Adult Congenital Heart Disease Committee of the Council on Clinical Cardiology and Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; and Council on Quality of Care and Outcomes Research . Diagnosis and management of noncardiac complications in adults with congenital heart disease: a scientific statement from the American Heart Association. Circulation 2017;136:e348–e392. [DOI] [PubMed] [Google Scholar]
- 14. Gilljam T, Mandalenakis Z, Dellborg M, Lappas G, Eriksson P, Skoglund K, Rosengren A. Development of heart failure in young patients with congenital heart disease: a nation-wide cohort study. Open Heart 2019;6:e000858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Wang T, Chen L, Yang T, Huang P, Wang L, Zhao L, Zhang S, Ye Z, Chen L, Zheng Z, Qin J. Congenital heart disease and risk of cardiovascular disease: a meta-analysis of cohort studies. J Am Heart Assoc 2019;8:e012030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Fedchenko M, Mandalenakis Z, Rosengren A, Lappas G, Eriksson P, Skoglund K, Dellborg M. Ischemic heart disease in children and young adults with congenital heart disease in Sweden. Int J Cardiol 2017;248:143–148. [DOI] [PubMed] [Google Scholar]
- 17. Mandalenakis Z, Rosengren A, Skoglund K, Lappas G, Eriksson P, Dellborg M. Survivorship in children and young adults with congenital heart disease in Sweden. JAMA Intern Med 2017;177:224–230. [DOI] [PubMed] [Google Scholar]
- 18. Botto LD, Lin AE, Riehle-Colarusso T, Malik S, Correa A; National Birth Defects Prevention Study . Seeking causes: classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Res A Clin Mol Teratol 2007;79:714–727. [DOI] [PubMed] [Google Scholar]
- 19. Liu S, Joseph KS, Luo W, León JA, Lisonkova S, Van den Hof M, Evans J, Lim K, Little J, Sauve R, Kramer MS; Canadian Perinatal Surveillance System (Public Health Agency of Canada) . Effect of folic acid food fortification in Canada on congenital heart disease subtypes. Circulation 2016;134:647–655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Lu F, Xue P, Zhang B, Wang J, Yu B, Liu J. Estimating the frequency of causal genetic variants in foetuses with congenital heart defects: a Chinese cohort study. Orphanet J Rare Dis 2022;17:2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Øyen N, Diaz LJ, Leirgul E, Boyd HA, Priest J, Mathiesen ER, Quertermous T, Wohlfahrt J, Melbye M. Prepregnancy diabetes and offspring risk of congenital heart disease: a nationwide cohort study. Circulation 2016;133:2243–2253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. R Core Team . R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2022. https://R-project.org [Google Scholar]
- 23. Mandalenakis Z, Karazisi C, Skoglund K, Rosengren A, Lappas G, Eriksson P, Dellborg M. Risk of cancer among children and young adults with congenital heart disease compared with healthy controls. JAMA Netw Open 2019;2:e196762. [DOI] [PubMed] [Google Scholar]
- 24. Thilén U, Jumatate R, Björkhem G, Jeremiasen I, Synnergren M, Bergman G. Årsrapport 2020 Nationellt Register för Medfödda Hjärtsjukdomar. Lund: SWEDCON; 2021. [Google Scholar]
- 25. Gurgey A, Ozyurek E, Gümrük F, Celiker A, Ozkutlu S, Ozer S, Bilgiç A. Thrombosis in children with cardiac pathology: frequency of factor V Leiden and prothrombin G20210A mutations. Pediatr Cardiol 2003;24:244–248. [DOI] [PubMed] [Google Scholar]
- 26. Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, Bernstein M, Brisson L, Cairney B, DeSai D, Israels S, Jardine L, Luke B, Massicotte P, Silva M. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251–1257. [PubMed] [Google Scholar]
- 27. Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007;5:692–699. [DOI] [PubMed] [Google Scholar]
- 28. Valente AM, Bhatt AB, Cook S, Earing MG, Gersony DR, Aboulhosn J, Opotowsky AR, Lui G, Gurvitz M, Graham D, Fernandes SM, Khairy P, Webb G, Gerhard-Herman M, Landzberg MJ; AARCC (Alliance for Adult Research in Congenital Cardiology) Investigators . The CALF (Congenital Heart Disease in Adults Lower Extremity Systemic Venous Health in Fontan Patients) study. J Am Coll Cardiol 2010;56:144–150. [DOI] [PubMed] [Google Scholar]
- 29. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim J-L, Reuterwall C, Heurgren M, Olausson PO. External review and validation of the Swedish national inpatient register. BMC Public Health 2011;11:450. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available from the sources stated in the article on request to the data providers, fulfilling legal and regulatory requirements, and with permission from the Swedish Ethical Review Authority.