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Pulmonary embolism and deep vein thrombosis—comorbidities and temporary provoking factors in a register‐based study of 1.48 million people

Abstract Background Knowledge on differences in patients who present with deep vein thrombosis (DVT) and those with pulmonary embolism (PE) is incomplete. Objective To determine comorbidities and temporary provoking factors in patients with a first‐time PE or DVT. Methods This was a nationwide Swedish registry‐based, retrospective, case‐control study including 298 172 patients with first‐time venous thromboembolism (VTE) and 1 185 079 controls matched for age, sex, and county of residence, free of VTE at the time of matching. Results Patients with PE were older than those with DVT (mean age, 69 vs 66 years) and included slightly more women (PE, 53.4% vs DVT, 52.1%). After multivariable adjustment for comorbidities (within 7 years) and temporary provoking factors (within 3 months), heart failure (PE: adjusted odds ratio [aOR], 2.64 [99% confidence interval [CI], 2.55‐2.73]; DVT: aOR, 1.66 [99% CI, 1.60‐1.72]), ischemic heart disease (PE: aOR, 1.51 [99% CI, 1.47‐1.56]; DVT: aOR, 1.01 [99% CI, 0.98‐1.04]), and chronic obstructive pulmonary disease (PE: aOR, 2.51 [99% CI, 2.40‐2.63]; DVT, 1.54 [99% CI, 1.47‐1.62]) were among diseases that showed higher odds ratios in patients with PE than in those with DVT, compared with controls. Comorbidities registered within 6 months were associated with higher aORs than those within 7 years. The highest population attributable risks for PE were for cancer (13.0%) and heart failure (11.7%). Conclusion Cardiopulmonary diseases, particularly with recent onset, imply a higher risk for PE, whereas orthopedic surgery and lower‐extremity fractures carry a higher risk of DVT.


Essentials
• There are few large-scale studies on deep vein thrombosis (DVT) and pulmonary embolism (PE).
• Patients with DVT or PE were compared with controls in a nationwide study of 1.48 million people.
• Diseases in heart and lungs were more common among patients with PE than in patients with DVT.
• Orthopedic surgery and fractures were more frequent in patients with DVT than in patients with PE.
The factor V Leiden mutation is more strongly correlated to risk of DVT, 12 while cardiac diseases have been shown to be a stronger risk for PE, which might also be the case for pulmonary conditions such as chronic obstructive pulmonary disease (COPD). 12,13 Previous studies on differences are either small, 14,15 are exclusively based on old data, 5,12,16 or only evaluated a limited number of comorbidities. 13,17 Given the difference in severity and mortality between PE and DVT, there is a need for a large, comprehensive study focusing on differences between patients with PE and patients with DVT.
The aim of this study was to determine age-specific incidence rates of PE and DVT as well as the prevalence of comorbidities and temporary provoking factors at the time of a first-time PE or DVT in comparison with a matched control population.

| Study population and design
This retrospective case-control study was based on four linked Swedish nationwide health and administrative registries. Sweden has a publicly financed health care system that provides low-cost    Table S1 in the Supplement. Comorbidities were defined as those registered within 7 years before the VTE event; recent comorbidities were defined as those registered within 6 months before the VTE event; and temporary provoking factors were defined as those registered within 3 months before the VTE event; all comorbidities and temporary provoking factors could be registered on the same discharge date as the index VTE.

| Statistical analysis
Categorical variables are presented as number with percentage, and continuous variables are presented as mean and standard deviation, as well as median with first and third quartiles. For comparisons between cases and controls, chi-square tests were used for dichotomous variables and t tests for continuous variables. All tests were two-tailed and with a 1% significance level.
Sex-and age-stratified incidence rates were calculated by dividing the VTE cases by individuals at risk (Swedish population) in the same age group for each year, using population data from the statistical database from Statistics Sweden. The total incidence rate was calculated by dividing the total number of first-time VTE cases by the total person-years at risk (inhabitants in Sweden each year).
Odds ratios (ORs) with 99% confidence intervals (CIs) were calculated separately for PE and DVT using conditional logistic regression according to case-control matching. Population attributable risk (PAR) was calculated according to Bruzzi et al. 19 PAR is used to estimate the reduction in percentage of PEs and DVTs in the population if a risk factor is eliminated.

Independent variables included in the multivariable analyses
were diagnoses of heart failure, ischemic heart disease, atrial fibrillation (AF); ischemic stroke; hemorrhagic stroke; COPD; cancer; inflammatory bowel disease; depression; psychosis; alcohol abuse; and (within 3 months previous to VTE) gastrointestinal surgery, musculoskeletal surgery, other major surgery, and hospitalization for trauma and lower extremity fracture (see Table S1 for definitions). Separate multivariable analyses were carried out for comorbidities registered within 7 years and within 6 months before the VTE diagnosis. In the multivariable analyses, when each risk factor was analyzed, adjustments were made for all other risk factors. ORs are presented as forest plots and ORs with 99% CIs are presented.
All statistical analyses were performed using SAS version 9 for Windows (SAS Institute Inc., Cary, NC, USA).

| Study population
In total, 298 172 patients in Sweden were registered with at least one diagnosis of VTE during the 32-year study period. Of these, 141 264 had a first diagnosis of PE (including 11 516 individuals with a PE and DVT registered on the same date), and 156 908 with a DVT ( Table 1).
In total, 220 634 patients were registered in the inpatient register and 76 559 in the outpatient register, whereas 979 patients were first registered with VTE in the Cause of Death Register (Table S2).
In 222 110 patients, VTE was registered as a primary diagnosis and as a secondary diagnosis in 76 062 patients. The matched control population comprised 1 185 079 individuals.

| Incidence rates
Age-and sex-specific incidence rates per 100 000 inhabitants for PE and DVT are shown in Figure 1 and Tables S3 and S4. Corresponding figures for any VTE (PE or DVT) are shown in Figure S1 and Table S5.
The total annual incidence rates in the population with a first VTE were 105.2 per 100 000 inhabitants, 49.8 per 100 000 for PE, and 55.4 per 100 000 for DVT.
For PE, the incidence increased from 0.9 to 290 per 100 000 inhabitants from ages 0 to 19 to 80 to 89 years ( Figure 1). PE was more common in women aged <40 years than in men of the same age but was more frequent in men than women aged 40 to 79 years.
For DVT, the incidence increased gradually from 1.5 per 100 000 at age 0 to 19 years to 323.6 per 100 000 among those aged ≥90 years ( Figure 1). Women aged <40 years and those aged ≥80 years had a slightly higher incidence of DVT than men of the same age.

| Comorbidity and temporary provoking factors
Baseline characteristics are presented separately for patients with DVT and PE in Table 1, with comorbidities registered within 7 years and temporary provoking factors registered within 3 months before the VTE event. On average, patients with PE were 3 years older than patients who had DVT (69 vs 66 years), and the proportion of women was slightly higher among patients with PE (53.4%) than those with DVT (52.1%). The most prevalent comorbidity among all patients was cancer (PE, 21.3%; DVT, 19.3%). Heart failure (PE, 18.9%; DVT, 10.3%) and ischemic heart disease (PE, 18.6%; DVT, 11.0%) were more common in patients with PE than in those with DVT.
Univariable ORs for patients with DVT and PE compared to controls are presented in Table 2, and ORs adjusted for various comorbidities registered within 7 years before the VTE and temporary provoking factors are presented in Figure 2A. The factors with the highest PARs for PE in the multivariable analysis were cancer (13.0%), heart failure (11.7%), ischemic heart disease (6.3%), and musculoskeletal surgery (7.2%). The highest PARs for DVT were found for cancer (11.9%) and musculoskeletal surgery (8.6%; Figure 2A).
We also examined the multivariable aORs and PARs for recently registered comorbidities (first registered within 6 months of the VTE diagnosis). The differences between PE and DVT were consistent, but the aORs were considerably higher in this analysis ( Figure 2B).  Note: Comorbidities were defined as a diagnosis registered within 7 years before the VTE event and temporary provoking factors were defined as a diagnosis registered within 3 months previous to the VTE event.

| DISCUSS ION
In this large retrospective case-control study based on data from several national registries, we found differences in comorbidities person-years for PE, and from 53 to 162 per 100 000 person-years for DVT, [9][10][11]20 and these are strongly dependent on age. 9,10,21 Our reported numbers are in the lower range of previous estimates, which is to be expected because our analysis encompassed all age groups, including children; however, the age-specific incidence rates are similar to smaller previous studies. 16,22,23 We also report a sex difference in VTE presentation. Patients with PE were more often women and older than patients with DVT. This is in line with previous studies. 10,24 Adjusted relative risk (RR) estimates vary considerably depending on the time frame within which the comorbidities have been registered. Higher RRs have been reported when including more recent comorbidities, as opposed to comorbidities registered over a longer period of time, 13 in line with our results. Previous studies also vary in terms of adjustment for confounding factors, with some studies adjusting for only age and sex 5 or for a limited number of potential risk factors and comorbidities. 16 In this study, the association of cardiac diseases with VTE was greater for PE than for DVT. This confirms previous findings from a large Danish register-based case-control study. In that study, patients with a diagnosis of myocardial infarction, heart failure, and AF within 3 months before their VTE had a markedly higher aOR for isolated PE than DVT alone, in comparison with controls. 13 When heart disease was recorded >3 months before the VTE, the aORs were considerably lower, in accordance with our results. 13 Other studies have found RRs for patients with heart failure ranging from 1.1 to for PE of 6.2%. 5,16,26 Previous studies with limited sample size have shown a tendency toward higher frequency of AF in patients with PE compared with those with DVT. 16,24,27 In recent years, most patients with AF are treated with anticoagulants, 28 and it is reasonable to believe that the correlation between AF and VTE is even stronger in patients with AF without anticoagulation.
Nearly 15% of acute exacerbations of COPD have been reported to be caused by PE, which is frequently unrecognized in the clinical setting. 29 We found COPD to have a stronger correlation with PE than with DVT. This is in line with previous, smaller studies. 16,30 There are several possible explanations for the higher OR of PE compared to DVT in patients with cardiopulmonary disease.
Overlapping symptoms between cardiopulmonary disease and PE could make clinicians more likely to investigate for PE. However, previous autopsy studies have shown the opposite, 31  proposed mechanism is the development of right atrial thrombi. 27,35 A bidirectional risk increase between VTE and AF has been shown. 36 We also report increased OR for ischemic and hemorrhagic stroke, inflammatory bowel disease, and psychiatric diseases. Stroke is a recognized risk factor for VTE with a markedly increased risk especially within the first month of the event. 37 The higher risk of VTE after hemorrhagic stroke, compared with that after ischemic stroke, was reported in a smaller study. 38 The increased risk of VTE in patients with inflammatory bowel disease has been reported previously. 39 Other potential limitations of this study include the lack of external validation of the VTE diagnoses. The validity of VTE diagnoses has been questioned. 44,45 In this study, we verified the diagnosis of VTE by retrieval of an anticoagulant prescription, a method previously suggested to increase the accuracy of VTE diagnosis. 44 However, this was possible only after July 2005. We have a low reported number of concomitant PE and DVT. This is probably due to underreporting; imaging of the lower-extremity veins is rarely performed in Sweden following the diagnosis of a PE. Therefore, we cannot study isolated PE compared to PE with DVT. In addition, patients admitted with a VTE could not be distinguished from those acquiring a VTE while in the hospital in our data.
Another limitation is the potential ascertainment bias. Patients with heart failure or COPD more often have shortness of breath than patients without these conditions. This could lead to more frequent chest imaging. The same could be true for patients with recent orthopedic surgery, with leg swelling, and imaging for DVT.
However, as mentioned above, the opposite could also be true since clinicians already have a plausible explanation for the symptoms.
The PARs for each factor correlated with VTE provide an estimate of the influence of each risk factor on a population level but should be interpreted with caution. VTE is a multifactorial disease, and both genetic and acquired risk factors interact to cause VTE. 46 It is also important to keep in mind that it is not possible to determine causality using these retrospective observational data.
Another limitation is the lack of information on body weight or body mass index. Obesity is a growing global problem and previous studies have found an increased risk of PE and DVT associated with obesity. 47 Poor socioeconomic status has been found to be associated with an increased risk of both VTE 48,49 and associated risk factors. 50 No such information is available in the included registries; hence, we were not able to adjust for this potential confounder.
The generalizability of the results is likely to be high for persons with similar thrombotic risk and socioeconomic situation as the Swedish population. However, the external reliability of the results for other populations is unknown.

| CON CLUS ION
In this study, patients with PE were considerably more likely to have cardiopulmonary disease, in particular of recent onset, while those who had recent surgery of the musculoskeletal system or lowerextremity fracture were more likely to be diagnosed with DVT.

ACK N OWLED G M ENTS
We would like to thank Bengt Bengtsson and Nils-Gunnar Pehrsson, Statistical consultant group, Gothenburg, Sweden, for consultation and performing the statistical analysis.

R EL ATI O N S H I P D I SCLOS U R E
KGS has received speaker's honoraria from Pfizer, Bristol-Meyers Squibb, Bayer and Leo Pharma. JS has received speaker's honoraria from Bayer. POH, AR, and SJ report no conflicts of interest.