Case-control study of venous thromboembolism risk in users of hormone replacement therapy
Authors: Edel Daly, Martin P Vessey, Rosemary Painter, Michael M Hawkins
Journal: The Lancet (1996)

The lack of data on the relation between use of hormone replacement therapy (HRT) and risk of venous thromboembolism (VTE) prompted us to undertake a hospital-based case-control study to address this question.1Daly E Vessey MP Hawkins MM Carson JL Gough P Marsh S Risk of venous thromboembolism in users of hormone replacement therapy.Lancet. 1996; 348: 977-980Summary Full Text Full Text PDF PubMed Scopus (834) Google Scholar In addition, we performed a small case-control study nested within the Oxford Family Planning Association (Oxford FPA) contraceptive study to provide additional data which are reported here. A description of the methods used in the Oxford FPA study has been given elsewhere.2Vessey MP Doll R Peto R Johnson B Wiggins P A long term follow-up study of women using different methods of contraception: an interim report.J Biosoc Sci. 1976; 8: 373-427Crossref PubMed Google Scholar In brief, 17 032 women were recruited during 1968–74 at 17 family planning clinics in England and Scotland. Those eligible for recruitment included white UK married women aged 25–39, who had been using oral contraceptives (OCs) for at least 5 months, or using a diaphragm or intrauterine device (IUD) for at least 5 months without previous use of OCs. About 99% of those approached agreed to participate and were followed up until 1994, with an annual loss of about 0·4. Only women who had used OCs for 8 or more years and those who had never used them were followed up beyond the age of 45. Data collected annually included use of HRT and hospital referrals. Applying the same inclusion and exclusion criteria as used in our larger study,1Daly E Vessey MP Hawkins MM Carson JL Gough P Marsh S Risk of venous thromboembolism in users of hormone replacement therapy.Lancet. 1996; 348: 977-980Summary Full Text Full Text PDF PubMed Scopus (834) Google Scholar we identified 18 women aged 45–64 with a first diagnosis of idiopathic deep-vein thrombosis (DVT), pulmonary embolism (PE), or both occurring between 1982 and 1993. Four cases with a history of recent (within 8 weeks) trauma were not excluded on this basis since available data were inadequate to ascertain whether trauma had resulted in prolonged bed-rest. Random selection of up to ten controls for each case, matched by age and clinic, and subject to the same exclusion criteria, yielded 161 eligible control women. Body-mass index (BMI), socioeconomic group, and a history of varicose veins were judged a priori to be potential confounding variables, and were included in conditional logistic regression models3Breslow NE Day NE Statistical methods in cancer research I: analysis of case-control studies. International Agency for Research on Cancer, Lyon1980: 192-246Google Scholar if they produced at least a 5% change in the estimated risk of VTE associated with HRT.1Daly E Vessey MP Hawkins MM Carson JL Gough P Marsh S Risk of venous thromboembolism in users of hormone replacement therapy.Lancet. 1996; 348: 977-980Summary Full Text Full Text PDF PubMed Scopus (834) Google Scholar Since none of the 18 cases had a history of hospital referral for varicose veins, it was not possible to adjust for this potential source of confounding. Overall, 22·2% of cases and 11·2% of controls had used HRT in the month before the case event date (defined as current use). Conditional logistic regression yielded an odds ratio (OR) of VTE associated with current HRT use of 2·3 (95% CI 0·6–8·1) compared with non-users (table). In a subgroup analysis omitting women with a history of recent trauma, the estimated OR of VTE associated with current HRT use compared with non-users was 3·5 (0·8–14·5). The data were too few for a valid analysis by duration of use.TableOdds ratios (OR) of venous thromboembolism in relation to current HRT use, with never users or non-users (never and past users combined) as reference groupComparisonCases/controlsAdjusted matched OR (95% CI)Relative to never usersNever use13/127*Past or never use of HRT was uncertain for 1 control who was not a current user. ORs are adjusted for BMI (categorised based on tertiles of control group values).1·0Past use1/15*Past or never use of HRT was uncertain for 1 control who was not a current user. ORs are adjusted for BMI (categorised based on tertiles of control group values).0·6 (0·1–5·1)Current4/182·2 (0·6–7·9)Relative to non-usersNon-user14/143*Past or never use of HRT was uncertain for 1 control who was not a current user. ORs are adjusted for BMI (categorised based on tertiles of control group values).1·0Current user4/182·3 (0·6–8·1)* Past or never use of HRT was uncertain for 1 control who was not a current user. ORs are adjusted for BMI (categorised based on tertiles of control group values). Open table in a new tab These results are in agreement with our larger case-control study published in this issue.1Daly E Vessey MP Hawkins MM Carson JL Gough P Marsh S Risk of venous thromboembolism in users of hormone replacement therapy.Lancet. 1996; 348: 977-980Summary Full Text Full Text PDF PubMed Scopus (834) Google Scholar Although the estimated OR of 2·3 in relation to current HRT use is not significantly different from unity, the 95% CI is entirely compatible with the estimated three-fold increase in risk observed in our larger study. Since idiopathic VTE is uncommon in this age-group, the absolute risk among HRT users will still be small, as we have discussed in more depth elsewhere in this issue. Given the benefits of HRT in relation to relief of menopausal symptoms and reductions in risks of osteoporotic fracture and coronary heart disease,4Daly E Vessey MP Barlow D Gray A McPherson K Roche M Hormone replacement therapy in a risk-benefit perspective.Maturitas. 1996; 23: 247-259Summary Full Text PDF PubMed Scopus (49) Google Scholar a small increase in risk of VTE may be an acceptable trade-off for many women who choose to use HRT. We thank the Knott Family Trust and the Medical Research Council for financial support. DEPARTMENT OF ERRORLamotrigine and toxic epidermal necrolysis-In this letter from Wadelius et al (Oct 12, p 1041) the sentence beginning the last paragraph should have read: "Two of the patients in this report reacted within 14 days …" Full-Text PDF