Smoking and venous thromboembolism: a Danish follow-up study

Authors

  • M. T. SEVERINSEN,

    1. Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg
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  • S. R. KRISTENSEN,

    1. Department of Clinical Biochemistry, Aalborg Hospital, Aarhus University Hospital, Aalborg
    2. Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Aalborg
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  • S. P. JOHNSEN,

    1. Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg
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  • C. DETHLEFSEN,

    1. Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Aalborg
    2. Department of Cardiology, Aalborg Hospital, Aarhus University Hospital, Aalborg
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  • A. TJØNNELAND,

    1. Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
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  • K. OVERVAD

    1. Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg
    2. Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Aalborg
    3. Department of Cardiology, Aalborg Hospital, Aarhus University Hospital, Aalborg
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Marianne Tang Severinsen, Department of Clinical Epidemiology, Aarhus University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark.
Tel.: +45 9932 6905; fax: +45 9932 6914.
E-mail: m.severinsen@rn.dk

Abstract

Summary. Background: Large-scale prospective studies are needed to assess whether smoking is associated with venous thromboembolism (VTE) (i.e. deep venous thrombosis and pulmonary embolism) independently of established risk factors. Objective: To investigate the association between smoking and the risk of VTE among middle-aged men and women. Methods: From 1993 to 1997, 27 178 men and 29 875 women, aged 50–64 years and born in Denmark, were recruited into the Danish prospective study ‘Diet, Cancer and Health’. During follow-up, VTE cases were identified in the Danish National Patient Registry. Medical records were reviewed and only verified VTE cases were included in the study. Baseline data on smoking and potential confounders were included in gender stratified Cox proportional hazard models to asses the association between smoking and the risk of VTE. The analyses were adjusted for alcohol intake, body mass index, physical activity, and in women also for use of hormone replacement therapy. Results: During follow-up, 641 incident cases of VTE were verified. We found a positive association between current smoking and VTE, with a hazard ratio of 1.52 (95% CI, 1.15–2.00) for smoking women and 1.32 (95% CI, 1.00–1.74) for smoking men, and a positive dose-response relationship. Former smokers had the same hazard as never smokers. Conclusions: Smoking was an independent risk factor for VTE among middle-aged men and women. Former smokers have the same risk of VTE as never smokers, indicating acute effects of smoking, and underscoring the potential benefits of smoking cessation.

Introduction

Venous thromboembolism (VTE) (i.e. deep venous thromboses, DVT, and pulmonary emboli, PE), is a common disease with substantial clinical implications [1–4].

Smoking is an established risk factor for arterial thrombosis, but data on its association with VTE are inconsistent. Recently a meta-analysis found a statistically insignificant odds ratio for VTE of 1.15 (95% CI, 0.92–1.44) for smokers compared with non-smokers [5]. Subsequently, a large case-control study found a positive association between smoking and VTE, with an odds ratio of 1.43 (95% CI, 1.28–1.60) [6]. Four prospective studies are available, two of which reported a positive association between smoking and VTE [7,8]. Further clarification of the effect of smoking on VTE risk requires large-scale epidemiological studies based on detailed prospective data on smoking, including dose, possible confounders, and verified VTE events.

The Danish Diet, Cancer and Health study is a prospective cohort study started in 1993 with the primary objective of investigating the etiological role of diet in the development of cancer. This prospective study includes very detailed data on smoking habits and relevant confounders according to VTE. In this follow-up we analyzed the effect of smoking, including dose, on the risk of VTE adjusted for potential confounders (i.e. obesity, physical activity, alcohol intake, and women’s use of hormone replacement therapy, HRT). We aimed to assess the association of smoking with both idiopathic and secondary VTE, as well as PE.

Methods

Study population

From December 1993 through to May 1997, 80 996 men and 79 729 women aged 50–64 years were invited to participate in the Danish prospective study ‘Diet, Cancer and Health’. The study has been described in detail elsewhere [9,10]. In short, eligible cohort members were born in Denmark, were living in the urban areas of Copenhagen and Aarhus, and were not, at the time of invitation to join the study, registered with a previous diagnosis of cancer in the Danish Cancer Registry. Participants were identified from computerized records of the Civil Registration System in Denmark, which has included all Danish inhabitants since 1968. The information includes a unique personal identification number in addition to name, address and vital status [11]. Diet, Cancer and Health and the present sub-study were approved by the regional ethics committees in Copenhagen and Aarhus, and by the Danish Data Protection Agency.

Outcomes and follow-up

We linked the Diet, Cancer and Health cohort with the Danish National Patient Registry, using the participants’ civil registration numbers. Based on the available hospital discharge history of each participant, we identified those who were registered with a discharge diagnosis of VTE (ICD-8: 450.99, 451.00, 451.08, 451.09, 451.99 and ICD-10: I26, I80.1–I80.9). Participants with a discharge diagnosis of VTE before enrollment into the Diet, Cancer and Health cohort were excluded. We reviewed medical records from participants with a first time VTE diagnosis in the Danish National Patient Registry from the time of enrollment into Diet, Cancer and Health until 30 June 2006. Information was obtained regarding symptoms, results of biochemical analyses, and diagnostic tests including duplex ultrasound, Doppler ultrasound, venography, echocardiography, ventilation-perfusion lung scan and CT scan. A VTE diagnosis was considered to be verified when typical clinical symptoms (unilateral swelling of leg, sagittal leg pain, discolored leg, dyspnea, chest pain, hyperventilation, increased plasma D-dimer, and hemoptysis) were combined with a confirmatory diagnostic test result (ultrasound, venography, echocardiography, ventilation-perfusion lung scan, or CT-scan). A leg thrombosis was classified as distal when the thrombus was located in the calf only, proximal when the thrombus was located in or above the popliteal vein, and pelvic when the thrombus was above the inguinal ligament. Upper extremity thromboses included thrombosis of the arm, axillary or subclavian veins. Concurrent DVT and PE were registered as PE.

Verified VTE events were classified as idiopathic or secondary (provoked) according to information in the medical records. The medical records include information regarding visits to outpatient clinics and inpatient clinics at the hospital. The complete medical record was reviewed carefully in every case. An event was regarded as secondary when any of the following criteria were registered in the medical record: a cancer diagnosis prior to, or within 3 months after, admission with VTE, surgery, trauma, travel (at least 5 h), acute medical disease with bed rest of at least 3 days (stroke, acute myocardial infarction, exacerbation of chronic lung disease, infection, activity in collagenous disease), immobilization, central vein catheter, or other provoking factors (vein obstruction, vessel anomaly) 3 months or less before the VTE. An event was regarded as idiopathic when the physician who examined the patient concluded that no provoking factors could be identified, or when the health of the patient was described as good without information indicating secondary VTE. The event was registered as ‘unclassified’ when information in medical records was sparse.

In the present study, we also included participants who died of VTE. We identified VTE deaths by linkage with the Danish National Death Registry (until 2003), and by review of death certificates from participants who died between 2003 and 2006. Only participants whose autopsy verified VTE were classified as VTE deaths.

Data on smoking and other lifestyle factors

Participants filled in detailed questionnaires about lifestyle factors at the time of enrollment into the Diet, Cancer and Health cohort. Data on smoking included smoking status (never, former and current smoker), tobacco doses, smoking duration, and time since cessation. Current tobacco consumption was calculated in grams per day using the following conversion factors: 1 cigarette equals 1 g, 1 cigar equals 4.5 g, 1 cheroot equals 3 g, and 1 pipe stop equals 3 g of tobacco. In addition, information on medication, education, work, diet, sports activities and alcohol consumption was obtained. The questionnaires were optically scanned. During the following interviews performed by trained laboratory technicians, information was amended. Technicians obtained anthropometric measurements in a standardized way. In 2000–2002, follow-up questionnaires were mailed to all surviving participants. Questions about diet and lifestyle changes were asked.

Participants for whom information was missing on one or more smoking or confounding variables and participants with unlikely smoking doses (more than 100 g day−1 tobacco) were excluded from analyses.

Statistical analysis

We assessed the association between smoking and risk of VTE separately for men and women, using Cox regression analyses. Age was used as the time axis to prevent confounding by age, with entry time defined as the subject’s age at recruitment. Study exit time was determined as age at VTE, date of death or emigration, or as 30 June 2006, whichever came first. Smoking doses were analyzed separately as a categorical exposure variable, and as a continuous exposure variable in restricted cubic spline models. Alcohol consumption, obesity, physical activity and women’s use of hormone replacement therapy (HRT) were considered as potential confounders. Therefore, all models included adjustment for these variables. In a supplementary model, we included education and performed analysis adjusted for categories of years in primary school and education after primary school in addition to the other adjustments. Model adequacy was assessed graphically and found appropriate in all analyses. Adjustment for physical activity was performed including activity as a dichotomous variable (i.e. above or below 30 min day−1 of activity, including bicycling). Body mass index (BMI) and alcohol consumption were included as continuous variables. Information on use of HRT by women was included as a dichotomous variable. The associations between smoking and VTE, idiopathic VTE, secondary VTE, secondary non-cancer VTE and PE were assessed.

Incidence rate of VTE was calculated for men and women according to tobacco consumption. We used the number of verified incident VTE events as the numerator and the sum of the individual person time at risk (follow-up time) as denominator. The incidence rates were standardized according to the age distribution among never smokers and were given as number of VTE events per thousand person-years at risk. We used stata version 9.2 (Stata Corporation, College Station, Texas, USA) for the statistical analyses.

Results

Study population and case ascertainment

In total, 27 178 men and 29 876 women joined the study (Fig. 1). All but 43 participants answered the questionnaire and participated in the following interview. We excluded 564 participants who were later identified in the Danish Cancer Registry as having a cancer diagnosis before the invitation, or in the weeks between invitation and the baseline examination. We also excluded 433 participants with a diagnosis of VTE before enrollment into the Diet, Cancer and Health study, which left 56 014 participants for analysis. Table 1 provides baseline characteristics of the participants.

Figure 1.

 Inclusions and exclusions before analysis of the association between smoking and VTE.

Table 1.   Baseline characteristics of the participants in the Diet, Cancer and Health cohort
 WomenMen
  1. 1Median (5–95 percentiles).

  2. 2Education, three categories of years in primary school: 7 years, 8–10 years, 11+ years.

  3. 3Education after primary school: no education after primary school, short, middle, long.

Number of participants29 34026 674
Age1, years56 (51–64)56 (51–64)
Smoking status, %
 Never smokers43.625.7
 Former smokers23.534.6
 Current smokers, < 15 g day−115.410.7
 Current smokers, 15–25 g day−114.917.5
 Current smokers, 25.1–35 g day−1 2.68.2
 Current smokers, > 35+ g day−13.4
Smoking duration1, if ever a smoker, years31 (5–45)33 (7–47)
Alcohol consumption1, g day−1 9 (0–42)19 (2–80)
Exercise > ½ h day−1, %4138
Hormone replacement therapy, %31Not relevant
Education2, %
 7 years31.434.8
 8–10 years50.241.5
 > 10 years18.523.7
Higher education3, %
 No19.310.0
 Short31.713.8
 Middle37.742.0
 Long11.334.1
Weight1, kg67 (53–91)82 (65–105)
Height1, cm164 (155–174)177 (166–188)
Body mass index1, kg m−225 (20–34)26 (21–33)

The median follow-up time was 10.2 years with an interquartile range from 9.6 to 10.8 years. During follow-up we verified 617 VTE events in the Danish National Patient Registry. Of these, 58% (n = 358) were DVT, and 42% (n = 259) were PE. Confirmed VTE events were characterized as idiopathic in 49% (n = 306) and secondary in 49% (n = 300) of cases. The remaining 2% (n = 11) could not be classified due to sparse information. Of the 56 014 participants, 4084 died during follow-up. We found 57 participants with an autopsy-proven PE diagnosis. However, 33 of these were already known from the Danish National Patient Registry with a prior verified VTE event. Our study, therefore, included 617 VTE events identified by review of medical records and another 24 PE events identified by autopsy. Thus in total, 641 confirmed VTE events were identified. The incidence rate of VTE was 1.15 (95% CI, 1.06–1.24) per 1000 person years.

Analyses

Table 2 shows the crude and adjusted hazard ratios of VTE for former smokers, current smokers, and for various smoking doses. The reference group is never smokers. The hazard ratio among current smokers was 1.52 (95% CI, 1.15–2.00) for women and 1.32 (95% CI, 1.00–1.74) for men. A positive association between smoking and VTE was found among women at all doses of tobacco, and among men at doses above 15 g day−1. The hazard ratio was highest for the highest doses of tobacco. Former smokers had the same risk as never smokers. For idiopathic VTE, we found a positive association with the highest dose of tobacco in both genders, with a hazard ratio of 4.34 (95% CI, 2.10–8.96) for women and 1.89 (95% CI, 0.97–3.68) for men. There was no association at lower doses of tobacco. For secondary VTE, we found a statistically significant positive association with current smoking for both genders. The association was also present for non-cancer-related secondary VTE. For PE, we found a less consistent positive association with current smoking for both genders. The incidence rates of VTE according to tobacco dose are given.

Table 2.   Hazard ratios (HR) of venous thromboembolism (VTE) and pulmonary embolism (PE), crude and adjusted for BMI, alcohol intake, recreational physical activity, and women’s use of HRT. Reference group is never smokers. Hazard ratios with 95% confidence interval are given. Number of cases in brackets. Incidence rates of VTE in number per 1000 person years according to tobacco dose standardized to age in never smoking group with 95% confidence interval
WomenNever smokedFormer smokerCurrent smoker. All dosesCurrent smoker < 15 g day−1Current smoker 15–25 g day−1Current smoker > 25 g day−1
All VTE (262)(100)(56)(106)(48)(44)(14)
Incidence rate0.80 [0.64–0.95]0.81 [0.60–1.01]1.14 [0.93–1.35]1.10 [0.80–1.39]1.03 [0.72–1.33]2.15 [1.01–3.29]
Crude HR10.96 [0.69–1.33]1.40 [1.06–1.85]1.28 [0.91–1.81]1.33 [0.93–1.90]2.78 [1.59–4.87]
Adjusted10.96 [0.69–1.33]1.52 [1.15–2.00]1.41 [1.00–2.00]1.43 [1.00–2.04]2.87 [1.63–5.05]
Adjusted*10.96 [0.69–1.33]1.46 [1.11–1.94]1.37 [0.97–1.94]1.38 [0.97–1.99]2.63 [1.46–4.74]
Idiopathic VTE (110)(45)(26)(39)(16)(14)(9)
Crude11.00 [0.61–1.62]1.15 [0.75–1.77]0.96 [0.54–1.70]0.94 [0.52–1.71]3.90 [1.90–7.99]
Adjusted11.03 [0.63–1.66]1.27 [0.83–1.96]1.07 [0.60–1.90]1.03 [0.56–1.88]4.34 [2.10–8.96]
Secondary VTE (135)(51)(26)(58)(28)(25)(5)
Crude10.86 [0.54–1.39]1.51 [1.03–2.19]1.46 [0.92–2.32]1.48 [0.92–2.40]1.97 [0.79–4.94]
Adjusted10.85 [0.53–1.37]1.60 [1.10–2.35]1.59 [1.00–2.53]1.57 [0.97–2.55]1.91 [0.75–4.85]
Secondary, non-cancer VTE (80)(32)(17)(31)(14)(14)(3)
Crude10.90 [0.50–1.63]1.29 [0.78–2.11]1.17 [0.63–2.20]1.32 [0.71–2.48]1.86 [0.57–6.08]
Adjusted10.89 [0.49–1.61]1.37 [0.83–2.26]1.29 [0.69–2.43]1.40 [0.74–2.65]1.74 [0.52–5.79]
PE (137)(57)(30)(50)(24)(18)(8)
Crude10.88 [0.57–1.38]1.15 [0.79–1.69]1.11 [0.69–1.79]0.95 [0.56–1.62]2.81 [1.34–5.89]
Adjusted10.90 [0.58–1.40]1.28 [0.87–1.88]1.25 [0.78–2.02]1.06 [0.62–1.80]2.95 [1.39–6.25]
MenNever smokedFormer smokerCurrent smoker. All dosesCurrent smoker < 15 g day−1Current smoker 15–25 g day−1Current smoker 25.1–35 g day−1Current smoker > 35 g day−1
  1. *Adjusted for primary school education (years in primary school) and higher education.

All VTE (363)(80)(128)(155)(34)(72)(30)(19)
Incidence rate1.17 [0.92–1.43]1.34 [1.10–1.58]1.50 [1.26–1.73]1.18 [0.78–1.58]1.53 [1.18–1.89]1.48 [0.96–2.00]2.23 [1.26–3.23]
Crude11.13 [0.85–1.49]1.28 [0.97–1.67]1.01 [0.67–1.51]1.33 [0.97–1.83]1.25 [0.82–1.91]1.94 [1.18–3.20]
Adjusted11.09 [0.82–1.44]1.32 [1.00–1.74]1.05 [0.70–1.57]1.40 [1.02–1.93]1.28 [0.83–1.95]1.97 [1.19–3.26]
Adjusted*11.09 [0.82–1.44]1.30 [0.99–1.71]1.04 [0.70–1.56]1.39 [1.00–1.92]1.27 [0.83–1.94]1.85 [1.10–3.10]
Idiopathic VTE (186)(46)(60)(80)(22)(33)(14)(11)
Crude10.96 [0.65–1.40]1.16 [0.81–1.67]1.16 [0.70–1.93]1.08 [0.69–1.69]1.00 [0.55–1.83]1.98 [1.02–3.82]
Adjusted10.91 [0.62–1.33]1.16 [0.80–1.68]1.19 [0.71–1.98]1.10 [0.70–1.74]0.96 [0.52–1.77]1.89 [0.97–3.68]
Secondary VTE (159)(30)(62)(67)(11)(35)(13)(8)
Crude11.40 [0.91–2.18]1.45 [0.94–2.23]0.85 [0.42–1.69]1.69 [1.04–2.76]1.47 [0.77–2.82]2.15 [0.98–4.69]
Adjusted11.38 [0.89–2.14]1.58 [1.02–2.44]0.91 [0.45–1.81]1.87 [1.14–3.06]1.61 [0.84–3.12]2.33 [1.06–5.11]
Secondary, non-cancer VTE (96)(17)(37)(42)(6)(21)(10)(5)
Crude11.50 [0.84–2.66]1.61 [0.92–2.83]0.82 [0.32–2.08]1.80 [0.95–3.41]1.99 [0.91–4.34]2.38 [0.88–6.45]
Adjusted11.43 [0.80–2.55]1.71 [0.97–3.03]0.88 [0.35–2.23]1.97 [1.03–3.75]2.08 [0.94–4.59]2.47 [0.90–6.73]
PE (138)(34)(46)(58)(15)(29)(9)(5)
Crude10.91 [0.57–1.46]1.11 [0.73–1.70]1.06 [0.56–1.98]1.27 [0.76–2.13]0.76 [0.33–1.73]1.31 [0.51–3.36]
Adjusted10.87 [0.54–1.39]1.16 [0.75–1.78]1.12 [0.60–2.11]1.38 [0.82–2.32]0.78 [0.34–1.79]1.33 [0.51–3.44]

Figure 2 shows the hazard ratios of VTE according to daily tobacco consumption for each gender. The reference groups are non-smoking women and men. The hazard ratio of VTE among women increased steeply for smoking more tobacco than 20 g day−1. Among men, the hazard ratio of VTE did not increase substantially before the dose exceeded 30 g day−1.

Figure 2.

 Hazard ratio of VTE according to daily tobacco dose in g/day modelled as a restricted cubic spline. Non-smokers are used as reference. Adjusted for BMI, alcohol and HRT (women only).

A total of 45 271 participants answered a follow-up questionnaire after 5 years. Data on smoking habits were complete for 44 379 participants, out of whom 1560 (3.5%) smoked more tobacco at follow-up than at baseline, 6612 (14.9%) smoked less at follow-up than at baseline, and 36 307 (81.8%) had not changed their smoking habits.

Discussion

In this large prospective study, we found current smoking to be positively associated with VTE, among both men and women. Former smokers had essentially the same risk of VTE as never smokers, indicating that the mechanism of smoking’s effect on VTE is acute. We found that smoking more than 20 g day−1 among women and 30 g day−1 among men was associated with a 150–300% higher hazard of VTE. Lower rates of tobacco consumption were associated with only a 10% to 40% higher hazard of VTE compared with never smokers, indicating a threshold difference for both men and women (Fig. 2).

Strengths and limitations of our study

This prospective study included 641 VTE events, and was one of the largest prospective studies on VTE. Data on smoking habits were detailed, and data from follow-up after 5 years showed a high degree of concordance with the baseline information. The changes were generally toward decreased consumption of tobacco at the follow-up, which may have resulted in an underestimation of risk. All VTE events were validated by review of medical records, and only objectively verified VTE events were included. The hospital system in Denmark is financed by taxation and almost everybody with VTE symptoms will be admitted to and examined in a hospital. The Danish National Patient Registry has collected nationwide data on all somatic hospital admissions since 1977. Since 1995, discharges from emergency departments and out-patient clinics have also been included in the registry [12]. The medical record includes information on visits to outpatient clinics as well as inpatients clinics. Obviously, there could be VTE events among participants that we missed. For example, because of a very low frequency of autopsy in Denmark (6% of all deaths in 2001) an unknown number of the participants died of PE. However, because smoking habits were unlikely to be associated with the chance of autopsy, any misclassification of fatal PE events was unlikely.

Smoking is an established risk factor for chronic obstructive lung diseases. Diagnosing PE is challenging, especially among patients with chronic obstructive lung disease, because perfusion/ventilation scintegraphy may not be conclusive in these patients. In addition, the most prominent symptom of PE, dyspnea, is normal for these patients. Dyspnea may be interpreted as a result of an exacerbation of the chronic obstructive lung disease, or as a result of pneumonia, which also occurs very often among these patients. The effect of smoking on PE may therefore be underestimated due to information bias.

Detailed information on a range of potential confounding factors was available for this study. However, adjusting for these factors in the statistical analyses had only a minor impact on the estimated hazard ratios. This indicates that residual confounding is not a likely explanation for the observed associations. However, Rosengren et al. [13] found a statistically significant positive association between PE and occupational class in men. Therefore we performed secondary analysis including adjustment for educational status and for years in primary school. The adjustments slightly weakened the association between smoking and VTE. Socioeconomic status may, however, directly influence smoking habits. Inclusion of socioeconomic status reduced the variation in smoking habits but also took into account potential confounding due to an association between socioeconomic status and smoking habits. However, as in all observational studies, we cannot completely rule out possible confounding by unknown factors.

Comparison with other studies

Our findings accord with the results from a number of other large-scale epidemiological studies. In a recent large case-control study, Pomp et al. [6] also found higher risk of VTE among smokers. Two prospective studies have found a positive association between smoking and venous thrombosis. Goldhaber et al. [7] investigated the association between smoking and PE among nurses. They reported 280 PE events during 16 years of follow-up. They found a significant positive association between smoking and PE among women who smoked more than 25 g day−1, and no association with lower tobacco doses, exactly as we did. Hansson et al. [8] also found a positive association between smoking more than 15 g day−1 of tobacco and the occurrence of VTE in a study of 851 men, followed for 30 years. The study included 65 VTE cases, with a substantial proportion, 21 of 65, diagnosed by autopsy, explaining why as many as 36 had PE. Also a substantial proportion (69%) was secondary VTE cases, of which 23 (35.5%) had cancer. After including comorbidity in a multivariate analysis, Hansson et al. were still able to find the association between smoking and VTE, in accordance with our findings.

In contrast, other prospective studies have not found an association between smoking and VTE. Tsai et al. combined data from two cohorts (the Atherosclerosis Risk in Communities study, ARIC, and the Cardiovascular Health study, CHS) in the Longitudinal Investigation of Venous Thromboembolism study (LITE). The ARIC cohort included men and women, 45–64 years of age, in which 130 VTE events occurred during follow-up. The CHS cohort included men and women above 65 years of age, in whom 85 VTE events occurred. Data in the LITE study included smoking status (never, former or current smoker). No association between VTE and smoking status was found. They also analyzed pack-years of smoking and found no association with VTE. The ARIC cohort data included current doses of tobacco. Analysis of this cohort showed a positive association between VTE and smoking more than 25 g day−1 of tobacco, compared with never smokers with adjusted hazard ratio of 1.68 (95% CI, 0.91–3.1) [14]. Glynn et al. also found no association between smoking and VTE in the prospective Physicians’ Health study. This study included American male physicians and 358 VTE events. The information on smoking included data on smoking status (current, former or never smoker), but not on tobacco dose [15].

We analyzed the dose-response relationship in a spline model that included current smoking dose as a continuous variable. The hazard ratio of VTE among women increased steeply for smoking more tobacco than 20 g day−1. Among men, the hazard ratio of VTE did not increase substantially before the tobacco dose exceeded 30 g day−1 (Fig. 2). Most previous studies did not include tobacco dose, only smoking status (never, former or current smoker). However, studies that did include tobacco dose also found the strongest association for the highest doses of tobacco, in line with our results. Our data suggest thresholds for the effect of smoking, at different levels for men and women. This could be explained, in part, by the differences between genders in body volume or liver metabolism. Further studies are needed to confirm these findings.

In both genders, we found a strong positive association between the highest doses of tobacco and idiopathic VTE (i.e. 4.34 [95% CI, 2.10–8.96] in women and 1.89 [95% CI, 0.97–3.68] in men), underscoring that the effect of smoking on the risk for VTE may not only be mediated through secondary diseases caused by smoking. We reviewed the updated discharge history from the Danish National Patient Registry for the 20 heavy smokers who suffered from idiopathic VTE. Of the 20 patients, one woman had a diagnosis of lung cancer 1 year later than the date of VTE, another woman had a diagnosis of breast cancer 6 years later and a man had a diagnosis of lung cancer 6 years later. The remaining 17 patients did not have diagnosis of cancer before April 2008 (mean of follow-up, 6 years from the date of VTE diagnosis). In secondary analysis we excluded the woman with a cancer diagnosis 1 year later than the VTE event because she might have had the cancer at the date of VTE (1 year before the cancer diagnosis) and found a hazard ratio of 3.85 (95% CI, 1.80–8.25) for idiopathic VTE in women smoking more than 25 g of tobacco per day. Our findings suggest a direct effect of heavy smoking on the risk of VTE. These findings are biologically plausible because smoking increases the level of coagulation factors in the blood and it also promotes activation of the inflammatory system, both of which are found to be associated with venous thrombosis [16,17]. We can not rule out possible confounding by unknown factors; however, it is difficult to imagine a strong confounder that only occurs among the heaviest smokers and that can explain our findings. Steffen et al. [18] showed that a diet including more plant food and fish and less meat is associated with lower incidence of VTE and there might be an association between smoking habits and diet; however, we think it is unlikely that poor diet explains our findings. Further studies are needed on this topic.

Among women the highest doses of tobacco (more than 25 g day−1) were positively associated with PE (i.e. hazard ratio of 3.07 [95% CI, 1.45–6.54]), whereas among men an insignificant positive association with PE was found (i.e. hazard ratio of 1.33 [95% CI, 0.51–3.44]) with the highest doses of tobacco (more than 35 g day−1). This may indicate that smoking promotes coagulation but is not involved in the process of embolization.

In conclusion, we found a positive association between smoking and VTE. The hazard ratio of VTE was especially high at tobacco doses above thresholds of 20 g day−1 of tobacco for women and 30 g day−1 for men. The smoking effect seems to be mediated by an acute effect because former smokers have the same risk as those who never smoked.

Acknowledgements

This study was financially supported by: the Research Foundation for Venous Diseases, Department of Hematology, Aalborg Hospital, Aarhus University Hospital; the Herta Christensens Research Foundation (Herta Christensens Fond); Specialist Heinrich Kopps Research Foundation (Speciallæge Heinrich Kopps Legat); and the Research Foundation of the Medical Profession in Northern Jutland (Nordjyllands Lægekredsforenings forskningsfond).

Disclosure and Conflict of Interests

The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors state that they have no conflict of interests.

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