SEARCH

SEARCH BY CITATION

Keywords:

  • venous thrombosis;
  • smoking;
  • hormone therapy;
  • interaction;
  • menopause

In postmenopausal women, oral hormone therapy (HT) is responsible for more than two venous thrombosis (VT) events per 1000 person-years of treatment (Rossouw et al, 2002). Recent evidence supports a synergistic effect of smoking and oral contraceptives on the risk of VT (Pomp et al, 2008). Because HT has similar components as oral contraceptives – oestrogen ± progestogen, albeit in lower doses – smokers could represent a group in whom the VT risk associated with HT is considerably increased. Although no interaction between smoking and HT was found in the Women's Health Initiative (WHI) clinical trial (Cushman et al, 2004), the small number of smoking VT cases and the selection of healthy participants in that trial may limit the validity and generalizability of this null finding. Our aim was to investigate the presence of this interaction in a large population-based study.

Among participants of the Heart and Vascular Health Study (HVH), a case–control study of cardiovascular outcomes among Group Health Cooperative (GHC) members in Washington State (Smith et al, 2004), we identified all post-menopausal women who suffered a first deep-venous thrombosis (DVT) and/or pulmonary embolism (PE), from 1 January 1995 to 31 December 2009. More than 90% of them agreed to participate (n = 1967), of whom >95% had positive diagnostic imaging test results. Women with no history of VT (n = 5146) were selected from a pool of randomly-chosen HVH controls. We excluded subjects who smoked pipes/cigars (n = 3), subjects with missing smoking data (n = 25), users of oral contraceptives during menopause (=31) and users of oestrogen patches or oral progestogen without oestrogen (n = 62).

The use of HT was determined from the GHC pharmacy database, from which we assumed 80% compliance with prescribing instructions (Smith et al, 2004). Information on smoking status came from a telephone interview for 58% of subjects and from the medical record review otherwise, with an agreement of 92% when both were available (Kappa = 0·85). Demographic characteristics, past medical history and details of the VT were abstracted from the entire GHC ambulatory medical record and the telephone interview.

Logistic regression models evaluated the association between HT use and the risk of VT, adjusting for matching factors (age, index years, hypertension), body mass index (BMI), recent diagnoses of cancer (within 5 years before to 3 months after index) and recent hospitalizations (within 6 months before index). Effect modification by smoking status was assessed by adding a multiplicative interaction term. Missing values for BMI (1%) and recent hospitalization (16%) were multiply imputed with a multivariate normal regression model generating 20 imputations (Schafer, 1999).

During the study period, 1926 cases suffered a DVT (n = 949), a PE (n = 690) or both (n = 287). Mean age and BMI of cases were 71 years and 29·5 kg/m2. Among 5066 controls, 90% were White, 9·4% were current smokers and 25·1% were using oral HT (9·9% with progestogen, almost exclusively medroxyprogesterone acetate). More than 85% of oestrogen preparations were conjugated equine oestrogen or esterified oestrogens. The median duration of use of oral HT after enrollment in GHC was 8·6 years for cases and 10·2 years for controls.

Overall, compared with non-users, women using oral HT had an increased risk of VT (odds ratio [OR] 1·35, 95% confidence interval [CI] 1·16–1·57). The smoking status of the participants did not significantly modify this association (Table 1). The OR for VT associated with HT was 1·42 (95%CI 1·16–1·74) among never smokers and 1·60 (95%CI 1·00–2·62) among current smokers, with no significant difference between these (OR ratio: 1·13, 95%CI 0·68–1·90, P = 0·55). Similarly, no interaction was found when comparing former with never smokers: ratio of ORs 0·84, 95%CI 0·61–1·14, P = 0·29.

Table 1. Association between hormone therapy and venous thrombosis, stratified by smoking status
 No hormone therapyAny hormone therapy
N [cases/controls]OR (95%CI)aN [cases/controls]OR (95%CI)aRatio of ORs (Interaction term)
  1. a

    Adjusted for matching factors (including age), recent diagnosis of cancer, recent hospitalization, and BMI.

  2. b

    Ratio of OR for current smokers to OR for never smokers.

  3. c

    Ratio of OR for former smokers to OR for never smokers. OR, odds ratio; 95%CI, 95% confidence interval.

Never smokers767/20621·0 (reference)222/7091·42 (1·16–1·74)Reference
Current smokers140/3711·0 (reference)38/1071·60 (1·00–2·62)1·13 (0·68–1·90)b
Former smokers599/13611·0 (reference)160/4561·16 (0·91–1·48)0·84 (0·61–1·14)c

We explored effect modification by dose, oestrogen type, progestogen use and smoking dose. In analyses restricting HT users to those taking the modal dose of oestrogen, the OR associated with HT was similar for both never and current smokers: 1·41 (95%CI 1·12–1·77) and 1·45 (95%CI 0·83–2·54), respectively (OR ratio 1·03, 95%CI 0·57–1·87). When oestrogen types were restricted to conjugated equine oestrogen, the ORs were not different between never and current smokers: OR 1·94 (95%CI 1·51–2·49) and OR 1·67 (95%CI 0·86–3·24), respectively, OR ratio 0·86 (0·43–1·74). Further, we found no interaction when stratifying HT use into unopposed and opposed HT and when stratifying current smoking into light and heavy smoking (<20 and >20 cigarettes/d).

Compared with never-smokers not using HT, we observed a 20% higher risk of VT in current smokers not using HT, a 40% higher risk of VT in never-smokers using the modal dose of HT and a 70% higher risk of VT in current smokers using HT (Table 2). There was no suggestion of a material additive interaction between smoking and HT.

Table 2. Individual and joint associations of current smoking and hormone therapy with venous thrombosis
Smoking statusHormone therapyaCasesControlsOR (95%CI)b
  1. a

    hormone therapy (HT) users are restricted to women receiving the most commonly prescribed daily dose of oestrogen (0·625 mg/d of conjugated equine oestrogen or equivalent).

  2. b

    Adjusted for matching factors (including age) and recent diagnosis of cancer, recent hospitalization and body mass index. OR, odds ratio; 95%CI, 95% confidence interval.

NeverNone76720621·0 (ref)
CurrentNone1403711·19 (0·92–1·53)
NeverHT1665421·41 (1·12–1·77)
CurrentHT26861·73 (1·03–2·91)

In this large, population-based, case–control study, smoking status was not found to modify the association between HT and VT. Smoking itself is a weak risk factor for incident VT (Blondon et al, 2013). Therefore, our results suggest that smoking is not an important factor for the development VT in users of oral HT, similarly to those of the WHI clinical trial (Cushman et al, 2004; Curb et al, 2006).

Our findings contrast with the observed synergistic effect of smoking and OC on the risk of VT (Pomp et al, 2008). This difference may be explained by the much lower potency of oestrogen found in HT preparations than in OC preparations, if a true biological interaction between oestrogen and smoking exists.

The increased risk of VT associated with oral HT in our data is not as strong as reported elsewhere (Sweetland et al, 2012). Reasons for this may include the use of esterified oestrogens (Smith et al, 2004), low oestrogen dose and the high proportion of prevalent users.

Oral oestrogens also increase the incidence of stroke and coronary heart disease in postmenopausal women (Rossouw et al, 2007), and smoking increases the risk of arterial cardiovascular events more than that of VT (Brækkan et al, 2012). For these reasons, caution is needed when prescribing oral HT to current smokers.

The strengths of our study include its population-based design, the ascertainment of VT events and the high-quality measures of HT use through pharmacy records. Its limitations include the low generalizability to non-White races and new HT users.

In conclusion, our data do not support the hypothesis that smoking modifies the association between HT and the risk of VT.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Conflicts of interest
  5. Disclaimer
  6. References

The Heart and Vascular Health Study is supported by the National Health Lung and Blood Institute grants HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, and HL95080. M. Blondon is supported by a fellowship for prospective researchers from the Swiss National Science Foundation.

Author contributions

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Conflicts of interest
  5. Disclaimer
  6. References

M Blondon: research design, analysis of data, drafting of the manuscript, approval of final version; KL Wiggins: acquisition of data, critical revisions of the manuscript and approval of its final version; A Van Hylckama Vlieg: interpretation of data, critical revisions of the manuscript and approval of its final version; B McKnight: research design, analysis of data, critical revisions of the manuscript and approval of its final version; BM Psaty: research design, interpretation of data, critical revisions of the manuscript and approval of its final version; KM Rice: research design, interpretation of data, critical revisions of the manuscript and approval of its final version; SR Heckbert: research design, interpretation of data, critical revisions of the manuscript and approval of its final version; NL Smith: research design, interpretation of data, critical revisions of the manuscript and approval of its final version.

Conflicts of interest

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Conflicts of interest
  5. Disclaimer
  6. References

Bruce M Psaty serves on a DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor), and on the Steering Committee of the Yale Open Data Access Project funded by Medtronic. Other authors report no conflicts of interest.

Disclaimer

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Conflicts of interest
  5. Disclaimer
  6. References

Part of this work has been presented as a poster at the 58th annual meeting of the Scientific & Standardization Committee of the ISTH in June 2012.

References

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. Conflicts of interest
  5. Disclaimer
  6. References
  • Blondon, M., Wiggins, K.L., McKnight, B., Psaty, B.M., Rice, K.M., Heckbert, S.R. & Smith, N.L. (2013) The association of smoking with venous thrombosis in women. A population-based, case–control study. Thrombosis and haemostasis, 109, 891896.
  • Brækkan, S.K., Hald, E.M., Mathiesen, E.B., Njølstad, I., Wilsgaard, T., Rosendaal, F.R. & Hansen, J.-B. (2012) Competing risk of atherosclerotic risk factors for arterial and venous thrombosis in a general population: the tromso study. Arteriosclerosis, thrombosis, and vascular biology, 32, 487491.
  • Curb, J.D., Prentice, R.L., Bray, P.F., Langer, R.D., Van Horn, L., Barnabei, V.M., Bloch, M.J., Cyr, M.G., Gass, M., Lepine, L., Rodabough, R.J., Sidney, S., Uwaifo, G.I. & Rosendaal, F.R. (2006) Venous thrombosis and conjugated equine estrogen in women without a uterus. Archives of internal medicine, 166, 772780.
  • Cushman, M., Kuller, L.H., Prentice, R., Rodabough, R.J., Psaty, B.M., Stafford, R.S., Sidney, S., Rosendaal, F.R. & Women's Health Initiative Investigators (2004) Estrogen plus progestin and risk of venous thrombosis. JAMA: The Journal of the American Medical Association, 292, 15731580.
  • Pomp, E.R., Rosendaal, F.R. & Doggen, C.J.M. (2008) Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. American journal of hematology, 83, 97102.
  • Rossouw, J.E., Anderson, G.L., Prentice, R.L., LaCroix, A.Z., Kooperberg, C., Stefanick, M.L., Jackson, R.D., Beresford, S.A.A., Howard, B.V., Johnson, K.C., Kotchen, J.M., Ockene, J. & Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA: The Journal of the American Medical Association, 288, 321333.
  • Rossouw, J.E., Prentice, R.L., Manson, J.E., Wu, L., Barad, D., Barnabei, V.M., Ko, M., LaCroix, A.Z., Margolis, K.L. & Stefanick, M.L. (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA: The Journal of the American Medical Association, 297, 14651477.
  • Schafer, J.L. (1999) Multiple imputation: a primer. Statistical methods in medical research, 8, 315.
  • Smith, N.L., Heckbert, S.R., Lemaitre, R.N., Reiner, A.P., Lumley, T., Weiss, N.S., Larson, E.B., Rosendaal, F.R. & Psaty, B.M. (2004) Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA: The Journal of the American Medical Association, 292, 15811587.
  • Sweetland, S., Beral, V., Balkwill, A., Liu, B., Benson, V.S., Canonico, M., Green, J., Reeves, G.K. & The Million Women Study Collaborators (2012) Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. Journal of Thrombosis and Haemostasis: JTH, 10, 22772286.