Spinal navigation for minimally invasive thoracic and lumbosacral spine fixation: implications for radiation exposure, operative time, and accuracy of pedicle screw placement.

PURPOSE: Navigation is emerging as a useful adjunct in percutaneous, minimally invasive spinal surgery (MIS). The aim of this study was to compare C-Arm navigated, O-Arm navigated and conventional 2D-fluoroscopy assisted MIS thoracic and lumbosacral spine fixation techniques in terms of operating time, radiation exposure and accuracy of pedicle screw (PS) placement. METHODS: Retrospective observational study of 152 consecutive adults who underwent MIS fixations for spinal instability: 96 2D-fluoroscopy assisted, 39 3D-C-Arm navigated and 27 using O-Arm navigated. RESULTS: O-Arm navigation significantly reduced PS misplacement (1.23%, p) compared to 3D-C-Arm navigation (7.29%, p = 0.0082) and 2D-fluoro guided placement (5.16%, p = 0379). 3D-C-Arm navigation was associated with lower procedural radiation exposure of the patient (0.4 mSv) than O-Arm navigation (3.24 mSv) or 2D-fluoro guidance (1.5 mSv). Operative time was comparable between three modalities. CONCLUSIONS: O-Arm navigation provides greater accuracy of percutaneous instrumentation placement with an acceptable procedural radiation dose delivered to the patients and comparable operative times. These slides can be retrieved under Electronic Supplementary material.

Time trends in breast cancer and menopause hormone therapy use in New Zealand.

OBJECTIVE: The publication of preliminary findings from the Women's Health Initiative (WHI) Study in 2002 suggested an increased risk of breast cancer among users of menopause hormone therapy (MHT). This resulted world-wide in a rapid and significant decline in the use of hormone therapy. It was later claimed that breast cancer incidence rates had fallen as a result of lower rates of hormone therapy use. Our aim was to investigate whether there was an association between changes in the use of hormone therapy and rates of breast cancer diagnosis in New Zealand subsequent to the publication of the WHI. METHOD: Validated prescription usage data along with breast cancer screening and cancer registration data were accessed. Time trends extending for 8 years after the publication of the WHI were assessed. RESULTS: The use of hormone therapy for managing menopausal symptoms fell by about 70% following the controversy about its safety. Breast cancer registration rates among women aged 50-59 years had started to fall in advance of this change in prescribing. Changes in other age groups appear to coincide with changes in the screening eligibility for the national breast screening program rather than use of hormone therapy. CONCLUSION: The time trend analysis does not support an association between changes in hormone therapy use and the incidence rate of breast cancer.

Decreased dose of radiation to dogs during acquisition of elbow radiographs using draped shielding.

Protective lead equivalent shielding of patients is not routinely used in veterinary radiology. The goal of this study was to determine whether the use of lead equivalent shielding results in a significant reduction in dose of radiation to dogs during acquisition of elbow radiographs. The authors measured radiation doses in the primary beam and over and under protective lead equivalent shielding that was placed at the level of the eyes, body and gonads during acquisition of elbow radiographs using 0.01 mSv sensitivity dosimetry badges. Shielding consisted of 0.5 mm lead equivalent aprons and thyroid shields placed over bodies and eyes, respectively. All badges in the primary beam-detected radiation. Shielding significantly decreased the dose of radiation with significantly less scatter and tube leakage radiation detected under compared with over shielding (P=0.0001). The dose of radiation detected over shielding was significantly greater than zero (P=0.0001), while that under shielding did not differ significantly from zero (P=0.09). Based on these results, the authors recommend protective shielding be used on veterinary patients during radiography.

Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate.

BACKGROUND: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. METHODS: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). RESULTS: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. CONCLUSIONS: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required.

Myocardial infarction risk and hormone replacement: differences between products.

OBJECTIVES: To establish the risk of myocardial infarction (MI) in users of hormone replacement therapy (HRT) compared with non-users and to compare the risk between different HRT regimens. METHODS: A population-based cohort and case-control study, and a case-control study nested within a cohort of HRT users, using the UK General Practice Research Database. Differences between HRT regimen, mode of administration and duration and recency of use were examined whilst adjusting for confounding. RESULTS: In the cohort and case-control study, 4537 cases of MI were identified in 2.62 million observed women years, cases were age-matched to 27,220 controls. In both studies, current and past HRT use were associated with reduced risk estimates for MI compared with no prior use. MIs were less likely to be fatal amongst women who had used HRT than amongst never users (OR(adj) 0.58; 95% CI 0.45-0.75). No difference in risk was seen between current and past use, oral and transdermal HRT or between different regimens (p>0.44). In the nested study, no difference was found in the association with MI risk between different oestrogen-progestogen combinations or between different combinations and tibolone. Unopposed oestrogen use was not associated with a decrease in risk compared with combined HRT. CONCLUSIONS: These results are consistent with previous observational studies in supporting the hypothesis that use of postmenopausal HRT is associated with a decrease in risk of acute myocardial infarction (AMI). Case fatality differed between HRT users and non-users, suggesting a protective effect of HRT. This study does not demonstrate a difference between regimens.

Detection and evaluation of intracranial aneurysms with 16-row multislice CT angiography.

AIM: The aim of this study was to assess the usefulness of 16-row multislice CT angiography (CTA) in evaluating intracranial aneurysms, by comparison with conventional digital subtraction angiography (DSA) and intraoperative findings. METHODS: A consecutive series of 57 patients, scheduled for DSA for suspected intracranial aneurysm, was prospectively recruited to have CTA. This was performed with a 16-detector row machine, detector interval 0.75 mm, 0.5 rotation/s, table speed 10mm/rotation and reconstruction interval 0.40 mm. CTA studies were independently and randomly assessed by two neuroradiologists and a vascular neurosurgeon blinded to the DSA and surgical findings. Review of CTA was performed on workstations with an interactive 3D volume-rendered algorithm. RESULTS: DSA or intraoperative findings or both confirmed 53 aneurysms in 44 patients. For both independent readers, sensitivity and specificity per aneurysm of DSA were 96.2% and 100%, respectively. Sensitivity and specificity of CTA were also 96.2% and 100%, respectively. Mean diameter of aneurysms was 6.3mm (range 1.9 to 28.1 mm, SD 5.2 mm). For aneurysms of less than 3 mm, CTA had a sensitivity of 91.7% for each reader. Although the neurosurgeon would have been happy to proceed to surgery on the basis of CTA alone in all cases, he judged that DSA might have provided helpful additional anatomical information in 5 patients. CONCLUSION: The diagnostic accuracy of 16-slice CTA is promising and appears equivalent to that of DSA for detection and evaluation of intracranial aneurysms. A strategy of using CTA as the primary imaging method, with DSA reserved for cases of uncertainty, appears to be practical and safe.

Venous thromboembolism associated with cyproterone acetate in combination with ethinyloestradiol (Dianette): observational studies using the UK General Practice Research Database.

PURPOSE: To derive risk estimates for venous thromboembolism (VTE) in women prescribed cyproterone acetate combined with ethinyloestradiol (CPA/EE), a drug licensed in the UK for the treatment of women with acne or hirsutism. CPA/EE provides a treatment option for women with polycystic ovary syndrome (PCOS). CPA/EE has been associated with an increased risk of VTE. METHODS: Using the General Practice Research Database, we conducted cohort and case-control analyses in all women aged 15-39 and then nested in a population of women of the same age with acne, hirsutism or PCOS. RESULTS: The incidence rate ratio (IRR) for VTE in women exposed to CPA/EE versus conventional combined oral contraceptives (COCs) was significantly raised (all women: 1.92; 95% CI: 1.22,2.88; nested: 2.51; 95% CI: 1.07,5.75). Using exposure to conventional COCs as the reference, the adjusted odds ratio (ORadj) for VTE associated with CPA/EE was 1.45 (95% CI: 0.80,2.64) in all women and 1.71 (95% CI: 0.31,9.49) in women with acne, hirsutism or PCOS. CONCLUSIONS: The risk of VTE associated with CPA/EE use does not differ significantly from that associated with the use of conventional COCs. These data are reassuring and together with knowledge of the risks associated with other treatments for acne, in particular, should influence prescribing practice.

Differences in the use of combined oral contraceptives amongst women with and without acne.

BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) provides a treatment option for women with acne, hirsutism or polycystic ovary syndrome (PCOS). CPA/EE may be prescribed as an oral contraceptive (OC), but is not licensed as such in the UK. The use of CPA/EE steadily increased after its introduction to the UK market in 1987, but there was a marked increase in its share of the OC market after 1995. METHODS: Using the General Practice Research Database, utilization patterns of CPA/EE and conventional oral contraceptives were compared in women aged 15-39 years, with or without acne or PCOS. RESULTS: Between 1994 and 1998, CPA/EE accounted for an increasing proportion of all OC use. The proportion of CPA/EE prescribed to women with acne declined between 1994 and 1998, whereas that prescribed to women with PCOS remained constant. The age-specific use of CPA/EE by women with acne or PCOS almost doubled. After 1995, there was a marked increase in the use of products containing levonorgestrel by women with acne or PCOS. CONCLUSIONS: A large proportion of CPA/EE is prescribed to women with acne and/or PCOS, although this proportion decreased between 1992 and 1998. This has important implications in CPA/EE risk assessment studies.

The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study.

BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) is licensed in the UK for the treatment of women with acne and hirsutism and is also a treatment option for polycystic ovary syndrome (PCOS). Previous studies have demonstrated an increased risk of venous thromboembolism (VTE) associated with CPA/EE compared with conventional combined oral contraceptives (COCs). We believe the results of those studies may have been affected by residual confounding. METHODS: Using the General Practice Research Database we conducted a cohort analysis and case-control study nested within a population of women aged between 15 and 39 years with acne, hirsutism or PCOS to estimate the risk of VTE associated with CPA/EE. RESULTS: The age-adjusted incidence rate ratio for CPA/EE versus conventional COCs was 2.20 [95% confidence interval (CI) 1.35-3.58]. Using as the reference group women who were not using oral contraception, had no recent pregnancy or menopausal symptoms, the case-control analysis gave an adjusted odds ratio (OR(adj)) of 7.44 (95% CI 3.67-15.08) for CPA/EE use compared with an OR(adj) of 2.58 (95% CI 1.60-4.18) for use of conventional COCs. CONCLUSIONS: We have demonstrated an increased risk of VTE associated with the use of CPA/EE in women with acne, hirsutism or PCOS although residual confounding by indication cannot be excluded.

Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care--the Triumph project.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is one of the most common conditions associated with ageing in men. BPH often presents as lower urinary tract symptoms (LUTS) due to difficulties in voiding and irritability of the bladder. We conducted a retrospective cohort study within the Integrated Primary Care Information (IPCI) database, a general practitioners database in The Netherlands, to assess the incidence of LUTS suggestive of BPH (LUTS/BPH) in the general population. MATERIALS: Our study population comprised all males, 45 years or older who were registered for at least 6 months prior to start of follow-up. The study period lasted from 1 January 1995 to 31 December 2000. Cases of LUTS/BPH were defined as persons with a diagnosis of BPH, treatment or surgery for BPH, or urinary symptoms suggestive of BPH that could not be explained by other co-morbidity. RESULTS: The study cohort comprised 80,774 males who contributed 141,035 person-years of follow-up. We identified 2181 incident and 5605 prevalent LUTS/BPH cases. The overall incidence rate of LUTS/BPH was 15 per 1000 man-years (95% CI: 14.8-16.1). The incidence increased linearly (r(2) = 0.99) with age from three cases per 1000 man-years at the age of 45-49 years (95% CI: 2.4-3.6) to a maximum of 38 cases per 1000 man-years at the age of 75-79 years (95% CI: 34.1-42.9). After the age of 80 years, the incidence rate remained constant. For a symptom-free man of 46 years, the risk to develop LUTS/BPH over the coming 30 years, if he survives, is 45%. The overall prevalence of LUTS/BPH was 10.3% (95% CI: 10.2-10.5). The prevalence rate was lowest among males 45-49 years of age (2.7%) and increased with age until a maximum at the age of 80 years (24%). CONCLUSIONS: The incidence rate of LUTS/BPH increases linearly with age and reaches its maximum at the age of 79 years.

Study of the association between ischemic heart disease and use of alpha-blockers and finasteride indicated for the treatment of benign prostatic hyperplasia.

OBJECTIVE: Given the high possibility of co-occurrence of benign prostatic hyperplasia (BPH) and cardiovascular disease, we evaluated whether patients using BPH drugs are at an increased risk of acute hospital admission for ischemic heart disease (IHD). METHODS: A nested case control study within a cohort of 4414 men (aged > or =30 years) who had a history of using BPH products between 1992 and 1998 was conducted. Cases were defined as men with a first record of an acute hospital admission for IHD during the study period; three controls were matched to each case on year of birth, pharmacy and calendar time (index date). RESULTS: The study population comprised 220 cases and 515 controls. Current use of alpha-blockers (adjusted odds ratio 1.0, 95% confidence interval: 0.5-2.2) or finasteride (adjusted odds ratio 0.3, 95% CI: 0.1-1.4) was not associated with hospital admission for IHD. Furthermore, current use of BPH drugs was not associated with IHD in patient subgroups (age, history of cardiovascular disease, diabetes), nor with duration of use prior to hospitalization. CONCLUSION: Although the power of the study was low, we found no evidence for an association between current use of BPH drugs and hospital admission for IHD. Therefore, our study seems to confirm the good cardiovascular safety profile of modern BPH drugs.

Evaluating adverse cardiovascular effects of drug treatment for benign prostatic hyperplasia (BPH): methodological considerations.

When studying the effects of drug exposure in diseases with a long asymptomatic clinical course, exposure classification may be biased by the gradually developing "visibility" of the disease. Benign prostatic hyperplasia (BPH) is such a disease. We found that cardiovascular morbidity is two times more prevalent in patients starting drug treatment for BPH when compared to age-matched population controls. This resulted in a difference of cardiovascular prognostic factors between the exposed and non-exposed. This feature can jeopardize the validity of non-randomized comparisons of drug effects. Moreover, the existence of non-treatment strategies, disease under-reporting, and an elderly population with a high baseline risk of experiencing (cardiovascular) outcome events were encountered as methodological problems. When studying adverse cardiovascular effects in patients using BPH products in a non-randomized fashion, an important question is whether we can measure in the database all relevant prognostic factors and use the information for statistical adjustment. This question is an important challenge to observational research and once again stresses the need for control of possible biases in choosing an appropriate study design.

Lower urinary tract symptoms suggestive of benign prostatic obstruction--Triumph: the role of general practice databases.

The Triumph project aims to document the current management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in general practice and to assess the effectiveness of the initial treatment options used. The first phase of the project will consider existing data sources in primary care. A patient's medical record will contain most, if not all, clinically relevant information, and databases combining the records from a network of computerised general practices can provide longitudinal data for complete populations, linking prescribing records to clinical information on disease progression and outcomes for individual patients. Database research can provide rapid information and offers the ability to conduct studies on a scale that would previously have been prohibited by both time and expense. Within the Triumph project, the THALES, General Practice Research Database (GPRD) and Integrated Primary Care Information (IPCI) databases are, or will be, used to examine the current management of LUTS/BPH in France, the UK and the Netherlands respectively. Preliminary results from the UK General Practice Research Database (GPRD) showed that LUTS/BPH incidence increased linearly from the ages of 45 to 85 years (r(2) = 0.992) and prevalence increased from 3.5% to 35% for men in their late 40s and 80s respectively. With treatment failure defined as a change to another medical therapy, catheterisation or prostatic surgery, and accounting for age and year variation, patients receiving the older alpha(1)-blockers (indoramin and prazosin) appeared to fail significantly earlier than those receiving finasteride. There was no significant difference between finasteride and the newer alpha(1)-blockers (tamsulosin, alfuzosin, terazosin and doxazosin). Patterns of changes between products from the THALES database in France were broadly similar to those seen in the UK.

How do symptoms indicative of BPH progress in real life practice? The UK experience.

OBJECTIVE: Lower urinary tract symptoms (LUTS) are usually, but not exclusively associated with benign prostatic hyperplasia (BPH). Using a population identified from the UK General Practice Research Database (GPRD), we describe the changes in the management of LUTS/BPH and assess the effectiveness of medical therapy between 1992 and 1998. METHODS: 61,364 men with LUTS/BPH and without a record of prostatic cancer were identified on the database. 14,195 were treated with an alpha1-blocker or finasteride. Treatment failure was defined as prostatic surgery, catheterisation or a switch in medical therapy. RESULTS: LUTS/BPH incidence increased linearly from the age of 45 to 85 years (r2 = 0.992) and prevalence increased from 3.5% to 35% for men in their late 40s and 80s respectively. Prostatectomy rates increased linearly from the age of 50 to 80 years (r2 = 0.984). Between 1992 and 1998, total treated-patient time had increased 3-fold, patients have been medically treated earlier and have increasingly been prescribed the LUTS/BPH-specific treatments finasteride, tamsulosin and alfuzosin in comparison to older treatments (indoramin, prazosin). In parallel, there has been a progressive increase in the interval between first diagnosis and prostatic surgery, and this interval is significantly longer for medically treated patients than those receiving no medical therapy. The intervals between the start and failure of medical therapy were significantly shorter for patients receiving indoramin and prazosin than for those receiving specific LUTS/BPH treatments. CONCLUSIONS: Between 1992 and 1998 there has been a significant lengthening of the period between first diagnosis of LUTS/BPH and surgery. This postponement of surgery is associated with earlier treatment and the increased use of specific LUTS/BPH treatments that appear more effective than older products in delaying treatment failure.

Venous thromboembolism and combined oral contraceptives: does the type of progestogen make a difference?

Venous thromboembolism (VTE) is rare in young women but is associated with the use of combined oral contraceptives (OCs). In 1995 and 1996, three studies showed a difference in the risk of VTE with third-generation OCs containing the progestogens, desogestrel or gestodene, compared with earlier formulations. However, the subsequent MediPlus study did not show any difference in the risk of VTE between users of third- and second-generation OCs. To re-examine the risks of VTE with various OCs, a nested case-control study was undertaken using the General Practice Research Database (GPRD). This study identified 293 cases and selected up to four controls matched for year of birth, practice, and event date. Adjustment for confounding variables included: body mass index, smoking, asthma, diastolic blood pressure, and a proxy for recent illness. The new analysis of the GPRD showed that there was no statistically significant difference in the risk of VTE among users of third-generation OCs compared with second-generation OCs containing levonorgestrel 150 microg plus ethinylestradiol 30 microg. Important associations with idiopathic VTE included: age, obesity, smoking, recent concurrent illness, and asthma. Thus, any difference previously noted between OCs containing desogestrel or gestodene and levonorgestrel are likely to be due to the healthy-user effect, prescribing bias and inadequate control of known confounding variables, such as age and obesity.

Mycobacterium chelonae sepsis associated with long-term use of an intravenous catheter for treatment of hyperemesis gravidarum. A case report.

BACKGROUND: Of the 1-2% of pregnant women who develop hyperemesis, the great majority are managed successfully with antiemetics and, when needed, short courses of parenteral medications. Only rarely will chronic parenteral therapy be necessary. Such therapy may be associated with significant complications. CASE: A 38-year-old woman, gravida 3, para 1, induced abortion 1, with a history of hyperemesis in her first pregnancy, developed recurrent hyperemesis at 9 weeks' gestation. After four admissions and a 5.45-kg weight loss at 12 weeks' gestation, a Groshong catheter was placed in the left subclavian vein. The patient was then managed with home droperidol infusions and intravenous hydration as needed. At 30 weeks' gestation she developed tender, erythematous nodules over her legs and right arm. Culture from a biopsy of the nodules grew Mycobacterium chelonae, as did the catheter tip. M chelonae is a ubiquitous, opportunistic, nontuberculous (atypical) mycobacterium. The patient responded slowly to clarithromycin. At 37 weeks she delivered a healthy, 4,080-g, male infant. Three months postpartum the nodules continued to resolve slowly on clarithromycin. CONCLUSION: When chronic parenteral therapy is required for hyperemesis gravidarum, attention must be given to potential complications. Indwelling catheters should be removed as soon as possible.

Medical therapy for benign prostatic hyperplasia: a review of the literature.

OBJECTIVE: To review the existing evidence regarding the efficacy and safety of medical therapy for lower urinary tract symptoms (LUTS) indicative of benign prostatic hyperplasia (BPH). To assess randomised controlled trials investigating the six alpha-adrenergic receptor antagonists (alpha-blockers), prazosin, alfuzosin, indoramin, terazosin, doxazosin, and tamsulosin, that benefit patients by relaxing prostatic smooth muscle, and the anti-androgen, finasteride, that mediates its more long-term benefits by reducing prostate size. RESULTS: This review suggests that both classes of drug offer significant improvement in criteria used to evaluate symptomatic BPH and can be effective whilst being acceptably safe. Furthermore, the therapeutic efficacy of all contemporary alpha-blockers appear similar, both in terms of symptom relief and urodynamic improvements. Randomised controlled trials have additionally demonstrated that finasteride therapy can provide improvement in terms of quality of life indices, prostate volume, and risks of progressing to acute urinary retention or prostatic surgery. While alpha-blockers have a rapid onset of action, likely to produce a therapeutic result within weeks, regardless of whether prostatic enlargement or bladder outlet obstruction is present, finasteride appears to be effective for more long-term therapy for up to 4 years, but only in alleviating symptoms when they are associated with a significantly large prostate. Neither finasteride nor the alpha(1a)-receptor-selective blocker, tamsulosin, are associated with the lowering of blood pressure and incidence of cardiovascular side effects that are apparent with other less selective alpha-blocker therapies such as dizziness and postural hypertension. They are, however, both associated with an increased risk of sexual dysfunction, albeit less than those associated with surgical intervention. Whereas tamsulosin is associated only with ejaculatory dysfunction, finasteride is additionally linked to decreased libido and impotence.

A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives.

AIMS: In October 1995 in response to the results of three studies, the Committee on the Safety of Medicines advised doctors and pharmacists that oral contraceptives containing desogestrel (DSG) and gestodene (GST) were associated with around a two-fold increase in the risk of thromboembolism compared with those containing other progestogens. The objective of this study was to estimate the risk of idiopathic venous thromboembolic disease (VTE) in users of combined oral contraceptives (COCs), to compare the risk between formulations and to examine the effect of using age banding as opposed to matching by exact year of birth. METHODS: A nested case control study was conducted using the General Practice Research Database. Women with a VTE event recorded between 1992 and 1997, who were treated with an anticoagulant, from consideration of their prescription records were likely to have been using a COC prescription on the day of the event and also had no exclusion factors, were deemed cases. For comparison with the previous studies, two nested case control studies were undertaken. Study 1 used controls matched by practice and year of birth. Study 2 used controls matched by practice and within 5 years age bands. RESULTS: We found an incidence of idiopathic VTE amongst users of combined oral contraceptives of 3.8 per 10 000 exposed women years. Incidence rates increased markedly after 35 years of age. The nested case-control study using controls matched by year of birth showed no significant difference in risk between the major COC formulations. With levonorgestrel (LNG) 150 microgram and ethinyloestradiol (EE) 30 microgram as the reference, the adjusted ORs for GST 75 microgram and EE 30 microgram was 1.3 (95% CI 0.8, 2.1), for DSG 150 microgram and EE 30 microgram it was 1.0 (95% CI 0.7, 1.7) and for DSG 150 microgram and EE 20 microgram it was 0.8 (95% CI 0.4, 1.6). Using less rigorous matching criteria, matching controls to cases within 5 years age bands, the ORs increased. When a mixed group of COCs, characterized by having LNG as the progestogen component was used as the reference category, there was an elevation in the ORs for the newer products. We found a significant association between idiopathic VTE and current smoking (OR 2.0 (1.4, 2.7)), BMI over 35 (OR 3.8 (1.8, 8.0)) and asthma (OR 1.9 (1.3, 2.9)). The OR for women who had proxy evidence of general ill health (indicated by the number of prescriptions issued) was 2.2 (1.7, 3.7). CONCLUSIONS: The results of this study indicate that a number of the characteristics of the women taking COCs affect the risk of VTE. There is no evidence to support the hypothesis that there is any difference in risk between COC formulations containing under 50 microg ethinyloestradiol.