Introduction
The incidence of venous thromboembolism (VTE) exceeds 1 per 1000 persons-years. More than 200,000 new cases of VTE occur in the United States each year, with a corresponding mortality rate of about 30% within 30 days [
1]. Among the survivors, 30% develop recurrent VTE [
1] and there is an increased mortality risk up to 8 years after the first thrombosis, [
1,
2]. Provoked VTE occurs in relation to identifiable risk factors, such as pregnancy, bone fractures, or surgery [
1,
3]. Unprovoked VTE shares some known risk factors with other cardiovascular diseases (CVDs) such as obesity, smoking [
4‐
7] and sleep-apnoea [
8‐
10]. Other risk factors for VTE include high body height [
11] and varicose veins [
1,
12‐
15]. Varicose veins and VTE has been suggested to share familial susceptibility [
16] and a genetic component of the familial clustering has been found for VTE, which makes heredity a potent risk factor [
17,
18] The risk of VTE also increases with age, especially among men aged > 50 years [
19,
20].
Poor self-rated health (SRH) has been associated with elevated serum inflammatory markers [
21] and has also been shown to be a predictor of depression [
22], stroke [
23] and other CVDs [
24], diabetes [
25], lung-cancer [
26] and all-cause mortality [
27,
28]. Thus, SRH is usually considered a valid and efficient measure of mental and physical health, especially in women [
29], although there is still a need to identify the validity limits of SRH for prediction of illness and mortality [
30].
A previous study investigating associations between the first VTE-episode and work-related disability showed a reduced risk for VTE when adjusted for good SRH. The authors discussed a possible association between low SRH and an elevated risk of incident VTE [
31].
To the authors’ knowledge, there are no previously published studies regarding the longitudinal association between SRH and incident VTE later in life among middle aged women. If such an association exists, it can be useful to include in risk assessment for incident VTE. In addition, as women often are more affected by poor SRH, they are particularly suitable for a study of a possible longitudinal association with VTE. SRH is also better at predicting somatic diseases in women than in men [
29].
The main aim of this cohort study was to examine the association between baseline SRH in middle-aged women (50–64 years) and incident VTE. The second aim was to analyze the association between lifestyle habits, i.e. physical activity, diet, smoking, alcohol consumption and VTE.
Results
During a follow-up time of 20.4 years, a total of 220 women were affected by VTE. The sum of the follow-up time was 85,645.836 years corresponding to a VTE incidence rate of 3.9 (95% CI 2.26–2.94) per 1000 person-years. There appeared to be statistically significant differences between women that were affected by incident VTE versus women that were not affected, i.e. differences in weight, height, waist-hip ratio, smoking, high and low activity level, dietary fiber, overall diet, SRH and varicose veins.
Women with incident VTE were on average taller, heavier and had a greater waist-hip ratio than those without incident VTE. There was a higher percentage of smokers and women with a low physical active level in the group with incident VTE. Regarding diet, there were only significant differences between the groups in dietary fiber intake and overall diet. Among women with incident VTE, a higher percentage had a low intake of dietary fiber and a less healthy overall diet. In the incident VTE-group there was also a greater number with varicose veins. The SRH differed significantly between the groups with a higher percentage rating their health as poor in the incident VTE group and this was even more obvious when categorizing into poor or good SRH.
An unadjusted Cox regression analysis was conducted (Table
3) with the aim to investigate if there were any significant associations between the variables that fell out with significance in the former analysis and incident VTE.
Table 3Univariate Cox regression with those variables which differed with a statistical significance in the baseline characteristics
Age | 1.05 | 1.00–1.10 | .033 | 5626 | 220 |
Marital | | | | 5606 | 220 |
Unmarried | 1.22 | .75–1.99 | .42 | | |
Married | Ref | | | | |
Divorced | .99 | .68–1.44 | .961 | | |
Widowed | 1.10 | .60–2.03 | .757 | | |
Education | | | | 5523 | 214 |
7–9 years | 1.42 | .99–2.00 | .052 | | |
10–12 years | Ref | | | | |
> 12 years | 1.18 | .86–1.63 | .294 | | |
Physical activity | | | | 5539 | 216 |
Very low | 2.27 | .92–5.59 | .075 | | |
Low | 1.56 | .88–2.74 | .125 | | |
Middle | Ref | | | | |
Middle-high | 1.02 | .76–1.35 | .914 | | |
High | .76 | .33–1.73 | .508 | | |
Very high | 6.34E–16 | 0 | 1.000 | | |
Activity high/low | 1.70 | 1.07–2.74 | .026 | 5539 | 216 |
Current smoker | 1.43 | 1.04–1.96 | .028 | 5533 | 216 |
Former smoker | .92 | .65–1.32 | .656 | | |
(Ref non-smoker) | | | | | |
Height | 1.03 | 1.00–1.06 | .013 | 5482 | 213 |
Waist circumference | 1.03 | 1.02–1.04 | 0 | 5041 | 198 |
Alcohol | | | | 5398 | 211 |
0g/w | 1.26 | .93–1.70 | .135 | | |
0–12g/w | Ref | | | | |
> 12g/w < 130g/w | .77 | .48–1.22 | .265 | | |
Sugar | | | | 5580 | 216 |
Daily | 1.70 | .97–3.01 | .066 | | |
Sometimes | Ref | | |
Avoids | 1.05 | .78–1.42 | .748 |
Fat in food | | | | 5353 | 205 |
Much | 1.46 | .89–2.40 | .132 | | |
Careful with | Ref | | | | |
Avoids | 1.11 | .82–1.49 | .509 | | |
Fiber | | | | 5547 | 215 |
Low intake | 1.16 | .42–3.13 | .771 | | |
Regularly | Ref | | | | |
Much | .77 | .58–1.03 | .078 | | |
Fruit | | | | 5594 | 219 |
Rarely | 1 | .76–1.32 | .985 | | |
Regularly | Ref | | | | |
Much | .76 | .24–2.41 | .644 | | |
Portion size | | | | 5240 | 198 |
Big | .81 | .45–1.46 | .481 | | |
Regular | Ref | | | | |
Small | .95 | .70–1.30 | .753 | | |
Diet | 1.38 | .94–2.00 | .095 | 5612 | 220 |
Family history | | | | 5477 | 216 |
Yes | 1.38 | .93–2.06 | .112 | | |
No | Ref | | | | |
Don’t know | 1.11 | .68–1.83 | .675 | | |
Acetylsalicylic | 1.52 | .38–6.12 | .554 | 5626 | 221 |
Diabetes | .62 | .28–1.41 | .261 | 5577 | 221 |
Hypertension | 1.17 | .67–2.05 | .581 | 5626 | 220 |
Varicose veins | 2.7 | 1.47–4.95 | .001 | 5626 | 220 |
Self-rated health | | | | 5529 | 216 |
1. Very poor | 2.78 | .99–7.80 | .051 | | |
2. | .71 | .25–1.99 | .516 | | |
3. | 1.15 | .66–2.01 | .628 |
4. | Ref | | |
5. | .83 | .55–1.25 | .374 |
6. | .7 | .47–1.05 | .087 |
7. Excellent | .54 | .34–.85 | .008 |
Poor self-rated health | 1.51 | 1.13–2.03 | .005 | 5529 | 216 |
Despite a relatively small difference in mean age between the groups at baseline, there was an increased risk for incident VTE for every year older at baseline (HR 1.05, 95% CI 1.00–1.10, p = 0.033). Cox regression analysis of SRH did not show any significant association with VTE-risk except for a decreased risk for those who rated their health as excellent (HR 0.54, CI 0.34–0.85, p = 0.008). When dichotomizing SRH into poor and good respectively, there was an increased risk for those who rated their health as poor (hazard ratio 1.51, CI 1.13–2.03, p = 0.005). When we dichotomized the variable physical activity, there was an increased incident VTE-risk for the low group (HR 1.70, CI 1.07–2.74, p = 0.026). Smoking at baseline was associated with a 43% increased risk of incident VTE (HR 1.43, CI 1.04–1.96, p = 0.028), smokers who had quit smoking at least one month before inclusion had a non-significant decreased risk of incident VTE (0.92, 0.65–1.32, p = 656). Waist circumference and varicose veins were associated with an increased risk as well (HR 1.03, CI 1.02–1.04, p = 0.000 and HR 2.70, CI 2.47–4.95, p = 0.001 respectively). Knowledge about family history of VTE (parents or siblings) was not associated with increased incident VTE-risk (HR 1.38, CI 0.93–2.06, p = 0.112). There was a non-significant trend towards an association between unhealthy diet and risk of incident VTE (HR 1.38, CI 0.44–2.00, p = 0.095). There was no significant association between hypertension before baseline and incident VTE (HR1.17, CI. 0.67–2.05, p = 0.581).
When the Cox regression results were adjusted for age (Table
4), model 1 showed a 51% increased risk for incident VTE if SRH was poor (HR 1.51, CI 1.12-2.02 p = 0.006). When we adjusted for lifestyle-related variables; physical activity, smoking, former smoking and waist circumference in model 2, the association between poor SRH and increased risk of incident VTE decreased to 16% and was not significant (HR 1.16, CI 0.84–1.61 p = 0.370). Even if low physical activity was associated with a significantly increased risk of incident VTE in the unadjusted model, this association was reduced and not significant when adjusting for other variables (HR 1.19, CI 0.62–2.04, p = 0.526). In model 3, adjusting for varicose veins and hypertension, the association between SRH and risk of incident VTE increased to 18% (HR 1.18, CI 0.85–1.65 p = 0.315). Even though the increased risk of age remained, it was not statistically significant in any of the models. In model 3, only the well-known risk factors had significant effect; smoking (HR 1.44, CI 1.02–2.03, p = 0.037), waist circumference (HR 1.03, CI 1.02–1.04, p = 0.000) and varicose veins (HR 2.60 CI 1.40–4.80, p = 0.002). When testing the proportional hazards assumptions for model 1, the global test was significant (p = 0.0390), which means that the hazards were not proportional over time. The second and third model showed proportional hazards (p = 0.1290, p = 0.1872) in the global test.
Table 4Multivariate Cox regression with the confounding variables that showed a significantly increased incident VTE-risk in the univariate test (Table
3)
Total (n) | 5529 | 4806 | 4806 |
Failures (n) | 216 | 188 | 188 |
Self-rated health (poor/good) | 1.51 | 1.16 | 1.18 |
CI | 1.12–2.02 | .84–1.61 | .85–1.65 |
p | .006 | .37 | .315 |
Age | 1.05 | 1.03 | 1.03 |
CI | 1.00–1.09 | .98–1.08 | .98–1.08 |
p | .048 | .193 | .200 |
Physical activity (low/high) | | 1.19 | .88 |
CI | | .69–2.04 | .65–1.19 |
p | | .526 | .421 |
Current smoker* | | 1.44 | 1.44 |
CI | | 1.02–2.03 | 1.02–2.03 |
p | .037 | .037 |
Former smoker* | .89 | .90 |
CI | .61–1.30 | .62–1.32 |
p | .549 | .588 |
Waist circumference | | 1.03 | 1.03 |
CI | | 1.02–1.04 | 1.02–1.04 |
p | | 0 | 0 |
Varicose veins (yes/no) | | | 2.6 |
CI | | | 1.40–4.80 |
p | | | .002 |
Hypertension (yes/no) | | | 1.12 |
CI | | | .63–1.98 |
p | | | .696 |
Proportional hazard assumption test | 0.039 | 0.1290 | 0.1872 |
Discussion
This is, to our knowledge, the first study that examines SRH as a predictor of incident VTE among middle-aged women in a well-defined cohort. In the multivariate model 3, there was a tendency towards an association between poor SRH and risk of incident VTE, but it was not statistically significant. Our results confirmed, however, an association with the already known risk factors varicose veins, smoking and waist circumference [
4,
11,
12,
34].
Braekkan et al. suggested that good SRH could attenuate the risk of VTE among people with a permanent work-related disability. They discussed the possibility that poor SRH may be affected by other diseases that in turn may increase the risk of VTE [
31]. If poor SRH was a good predictor of incident VTE, we ought to have observed a significant association in this cohort comprising only women. However, we did not observe any significant association. The reason for this assumption is that SRH has been suggested to be better at predicting different diseases in women than in men [
29]. What is notable, however, is that when we excluded those who got affected with VTE between baseline and 5 years follow up, the risk for VTE among those with poor SRH was increased even in the fully adjusted model (HR 1.38, CI 0.96–1.99, p = 0.086). This shows that there may be a significant association during long time follow-up, but we were unable to capture it in this study. Regarding the association between varicose veins and VTE, Chang et al. [
15] pointed out, that it is unknown whether this association is causal or represents a common set of risk factors. Considering the strong association, it can be argued for the need of preventive actions in people with varicose veins. This is especially pertinent since about 40% of adults are affected by varicose veins, and even a higher share among those who are obese and women with more than two pregnancies [
37].
Low physical activity, i.e. less than 30 min vigorous activity 5 days a week [
33], was significantly associated with increased risk of incident VTE in the unadjusted model, but not in the multivariate model 3 (Table
4). This may have been due to lack of power. There were no significant associations between self-reported intake of healthy or unhealthy food, alcohol, portion size and risk of incident VTE, which is consistent with previous studies among women, even if there have been suggested associations between unhealthy food, activity level and overweight/obesity [
38,
39]. We neither noticed any significant associations between hypertension and risk for VTE, or differences between those who got affected with incident VTE and those who did not, regarding hypertension. Healthy food and a proper amount of physical activity do not seem to prevent VTE, but a healthy way of living may help to prevent a large waist circumference, which turned out to be associated with incident VTE in our study.
Why SRH is associated with arterial CVDs [
24] but not with VTE in the present study may have several explanations. It is possible that the study participants changed their way of living after baseline measurements including questionnaires if they became more aware of their negative habits and changed them [
40,
41]. Another explanation could be that many risk factors are different between VTE and arterial diseases [
7], although some risk factors are shared. It is thus possible that SRH is a risk factor for arterial diseases but not for VTE. SRH may also be a weak risk factor for VTE and that a larger study might find a significant association with SRH, albeit weaker than for arterial disease. Finally, it is possible that SRH does not represent an additional risk factor for VTE once the other risk factors have been taken into account.
Strengths
This study is comprised of a well-defined cohort and it contained both self-reported and anthropometric values combined with information from registers. We censored participants who were affected by cancer or any cardiovascular disease before the first VTE occurrence during follow-up and diagnosed hypertension and varicose veins after baseline in order to decrease the risk of influences on VTE-risk and poor SRH.
Limitations
A limitation is that SRH was only measured at baseline as SRH may change over time. However, a study by Sargent-Cox et al. reported that SRH in women remained relatively stable compared with increasing age, whereas men´s ratings tended to become more negative [
42]. The study was performed in middle-aged women living in a certain area, which limits the generalizability to a wider context, e.g. to men and women in other ages than those enrolled. Due to a limited number of VTE events, we could not compare the occurrence of the different VTE-forms deep vein thrombosis (DVT) and pulmonary embolism (PE) between the groups. For the same reason, we could not perform any sub-analysis with provoked and unprovoked VTE.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.