Risk factors associated with mortality from breast cancer in Waikato, New Zealand: a case-control study.

OBJECTIVES: The aim of this study is to identify key characteristics associated with mortality from breast cancer among women with newly diagnosed breast cancer in New Zealand (NZ). STUDY DESIGN: Case-control study. METHODS: All primary breast cancers diagnosed between 01/01/2002 and 31/12/2010 in Waikato, NZ, were identified from the Waikato Breast Cancer Register. A total of 258 breast cancer deaths were identified from 1767 invasive cancers diagnosed over this period. RESULTS: Breast cancer deaths (n = 246) were compared with an age and year of diagnosis matched control group (n = 652) who were alive at the time of the death of the corresponding case and subsequently did not die from breast cancer. Diagnosis through symptomatic presentation, advanced stage, higher grade, absent hormone receptors (i.e. oestrogen and progesterone) and HER-2 amplification were associated with significantly higher risks of breast cancer mortality in bivariate analysis. Tumour stage, grade and hormone receptor status remained significant in the multivariable model, while mode of detection and HER-2 status were non-significant. In the bivariate analysis, Maori women had a higher risk of breast cancer mortality compared to NZ European women (OR 1.34) which was statistically non-significant. However in the adjusted model, risk of mortality was lower for Maori compared to NZ European women, although this was not significant statistically (OR 0.85). CONCLUSIONS: Mortality pattern from breast cancer in this study were associated with established risk factors. Ethnic inequity in breast cancer mortality in NZ appears to be largely attributable to delay in diagnosis and tumour related factors. Further research in a larger cohort is needed to identify the full impact of these factors on ethnic inequity in breast cancer mortality.

Risk of myocardial infarction in men and women with type 2 diabetes in the UK: a cohort study using the General Practice Research Database.

AIMS/HYPOTHESIS: Our primary aim was to establish reliable and generalisable estimates of the risk of myocardial infarction (MI) for men and women with type 2 diabetes in the UK compared with people without diabetes. Our secondary aim was to investigate how the MI risk associated with diabetes differs between men and women. METHODS: A cohort study using the General Practice Research Database (1992-1999) was carried out, selecting 40,727 patients with type 2 diabetes and 194,913 age and sex-matched patients without diabetes. Rates of MI in men and women with and without diabetes were derived, as were hazard ratios for MI adjusted for known risk factors. RESULTS: The rate of MI in men with type 2 diabetes was 19.74 (95% CI 18.83-20.69) per 1,000 person-years compared with 16.18 (95% CI 15.33-17.08) per 1,000 person-years in women with type 2 diabetes. The overall adjusted relative risk of MI in diabetes versus no diabetes was 2.13 (95% CI 2.01-2.26) in men and 2.95 (95% CI 2.75-3.17) in women and decreased with age in both sexes. Women with type 2 diabetes aged 35 to 54 years were at almost five times the risk of MI compared with women of the same age without diabetes (HR 4.86 [95% CI 2.78-8.51]). CONCLUSIONS/INTERPRETATION: This study has demonstrated that women with type 2 diabetes are at a much greater relative risk of MI than men even when adjusted for risk factors.

Risk of stroke in people with type 2 diabetes in the UK: a study using the General Practice Research Database.

AIMS/HYPOTHESIS: Risk estimates for stroke in patients with diabetes vary. We sought to obtain reliable risk estimates for stroke and the association with diabetes, comorbidity and lifestyle in a large cohort of type 2 diabetic patients in the UK. MATERIALS AND METHODS: Using the General Practice Research Database, we identified all patients who had type 2 diabetes and were aged 35 to 89 years on 1 January 1992. We also identified five comparison subjects without diabetes and of the same age and sex. Hazard ratios (HRs) for stroke between January 1992 and October 1999 were calculated, and the association with age, sex, body mass index, smoking, hypertension, atrial fibrillation and duration of diabetes was investigated. RESULTS: The absolute rate of stroke was 11.91 per 1,000 person-years (95% CI 11.41-12.43) in people with diabetes (n = 41,799) and 5.55 per 1,000 person-years (95% CI 5.40-5.70) in the comparison group (n = 202,733). The age-adjusted HR for stroke in type 2 diabetic compared with non-diabetic subjects was 2.19 (95% CI 2.09-2.32) overall, 2.08 (95% CI 1.94-2.24) in men and 2.32 (95% CI 2.16-2.49) in women. The increase in risk attributable to diabetes was highest among young women (HR 8.18; 95% CI 4.31-15.51) and decreased with age. No investigated comorbidity or lifestyle characteristic emerged as a major contributor to risk of stroke. CONCLUSIONS/INTERPRETATION: This study provides risk estimates for stroke for an unselected population from UK general practice. Patients with type 2 diabetes were at an increased risk of stroke, which decreased with age and was higher in women. Additional risk factors for stroke in type 2 diabetic patients included duration of diabetes, smoking, obesity, atrial fibrillation and hypertension.

Mortality in people with type 2 diabetes in the UK.

AIMS: Under-reporting of diabetes on death certificates contributes to the unreliable estimates of mortality as a result of diabetes. The influence of obesity on mortality in Type 2 diabetes is not well documented. We aimed to study mortality from diabetes and the influence of obesity on mortality in Type 2 diabetes in a large cohort selected from the General Practice Research Database (GPRD). Methods A cohort of 44 230 patients aged 35-89 years in 1992 with Type 2 diabetes was identified. A comparison group matched by year of birth and sex with no record of diabetes at any time was identified (219 797). Hazards ratios (HRs) for all-cause mortality during the period January 1992 to October 1999 were calculated using the Cox Proportional Hazards Model. The effects of body mass index (BMI), smoking and duration of diabetes on all-cause mortality amongst people with diabetes was assessed (n = 28 725). Results The HR for all-cause mortality in Type 2 diabetes compared with no diabetes was 1.93 (95% CI 1.89-1.97), in men 1.77 (1.72-1.83) and in women 2.13 (2.06-2.20). The HR decreased with increasing age. In the multivariate analysis in diabetes only, the HR for all-cause mortality amongst smokers was 1.50 (1.41-1.61). Using BMI 20-24 kg/m(2) as the reference range, for those with a BMI 35-54 kg/m(2) the HR was 1.43 (1.28-1.59) and for those with a BMI 15-19 kg/m(2) the HR was 1.38 (1.18-1.61). CONCLUSIONS: Patients with Type 2 diabetes have almost double the mortality rate compared with those without. The relative risk decreases with age. In people with Type 2 diabetes, obesity and smoking both contribute to the risk of all-cause mortality, supporting doctrines to stop smoking and lose weight.

Emergency management of diabetes and hypoglycaemia.

OBJECTIVE: Hypoglycaemia is the commonest diabetic emergency and is associated with considerable morbidity and mortality. This study looked at the use of the emergency services by people with diabetes, with particular reference to hypoglycaemia. METHOD: Data were collected on all attendances related to diabetes at accident and emergency departments at two district general hospitals in Surrey, UK, over a one year period. RESULTS: Hypoglycaemia was the commonest reason for attendance at accident and emergency. The management of hypoglycaemia was variable, the most frequent method of treatment being intramuscular glucagon administered by the ambulance service. Ninety per cent of patients with hypoglycaemia were either discharged or self-discharged from the accident and emergency department, and half of these patients had no follow up arranged. CONCLUSIONS: Hypoglycaemia is the commonest diabetic emergency and current management is suboptimal. Standardised protocols and better education of healthcare professionals and patients are required.

All-cause mortality rates in patients with type 1 diabetes mellitus compared with a non-diabetic population from the UK general practice research database, 1992-1999.

AIMS/HYPOTHESIS: We compiled up to date estimates of the absolute and relative risk of all-cause mortality in patients with type 1 diabetes in the UK. MATERIALS AND METHODS: We selected patients with type 1 diabetes (n=7,713), and for each of these diabetic subjects five age- and sex-matched control subjects without diabetes (n=38,518) from the General Practice Research Database (GPRD). Baseline was 1 January 1992; subjects were followed until 1999. The GPRD is a large primary-care database containing morbidity and mortality data of a large sample representative of the UK population. Deaths occurring in the follow-up period were identified. RESULTS: The study comprised 208,178 person-years of follow-up. The prevalence of type 1 diabetes was 2.15/1,000 subjects in 1992 (mean age 33 years, SD 15). Annual mortality rates were 8.0 per 1,000 person-years (95% CI 7.2-8.9) in type 1 diabetic subjects compared with 2.4 per 1,000 person-years (95% CI 2.2-2.6) in those without diabetes (hazard ratio [HR]=3.7, 95% CI 3.2-4.3). The increased mortality rates in patients with type 1 diabetes were apparent across all age-bands. The HR was higher in women (HR=4.5, 95% CI 3.5-5.6 compared with non-diabetic women) than men (HR=3.3, 95% CI 2.7-4.0), such that the sex difference (p<0.0001) in mortality in the non-diabetic population was abolished (p=0.3) in the type 1 diabetic patients. The predominant cause of death in patients with type 1 diabetes was cardiovascular disease. CONCLUSIONS/INTERPRETATION: Despite advances in care, UK mortality rates in the past decade continue to be much greater in patients with type 1 diabetes than in those without diabetes.

Antibiotic failure in the treatment of urinary tract infections in young women.

Urinary tract infections (UTIs) are a common problem in young women. The aim of this study was to describe the pattern of antibiotic prescribing to young women presenting with new UTIs and to investigate the proportion who required further treatment if prescribed antibiotics. A secondary aim was to investigate whether the likelihood of treatment failure varied between different antibiotics and, in the case of trimethoprim (the antibiotic most frequently prescribed for UTIs) between prescriptions of different duration. The study included all women aged 15-44 years registered on the UK General Practice Research Database. All diagnoses of UTI or cystitis with an associated prescription for an antibiotic were identified. A further prescription of an antibiotic within 28 days was taken to indicate failure of the initial treatment. Overall, 14% of 75045 newly treated patients with UTI received a second antibiotic within 28 days. Older women, aged 35-44, pregnant patients and those with diabetes were significantly more likely to require further treatment. With trimethoprim as the reference antibiotic, after 28 days patients prescribed amoxicillin were significantly more likely to require a second course of antibiotics. Those prescribed co-trimoxazole were significantly less likely to require further treatment. In each case the difference in failure rate was small and may be of little clinical significance. There was no significant difference between trimethoprim and nitrofurantoin, norfloxacin, ciprofloxacin or the cephalosporins. Three-day prescriptions for trimethoprim appeared as effective as those for 5 or 7 days. This study gives some observational evidence of the effectiveness of antibiotic prescribing in young women with UTIs and shows that between 12% and 16% of patients will return within 28 days for further treatment, irrespective of the antibiotic prescribed initially.

The risk of liver damage associated with minocycline: a comparative study.

Using the General Practice Research Database, the authors performed (1) a cohort analysis comparing the incidence of liver dysfunction in new users of minocycline with new users of oxytetracycline/tetracycline and (2) a case control study assessing antibiotic exposure in new cases of liver dysfunction and controls without liver dysfunction. In new users, the incidence of liver dysfunction in those exposed to minocycline was 1.04 cases/10,000 exposed person months (EPM) and 0.69 cases/10,000 EPM in those exposed to oxytetracycline/tetracycline (relative risk 1.51 [CI95: 0.63, 3.65]). The risk in both groups was greatest in the first month of use. The adjusted odds ratio (ORadj) of liver dysfunction associated with exposure to minocycline compared with nonuse was 2.10 (CI95: 1.30, 3.40); for oxytetracycline/tetracycline, the ORadj was 1.46 (CI95: 0.81, 2.64); and for exposure to erythromycin, the ORadj was 1.64 (CI95: 0.71, 3.80). The authors thus support a weak association between the use of oral antibiotics and liver dysfunction in patients with acne. The risk associated with exposure to minocycline appears to be very small. The cohort analysis demonstrated that any risk associated with minocycline was not significantly greater than that associated with oxytetracycline/tetracycline exposure.

Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database.

OBJECTIVE: To determine the incidence of venous thromboembolism in pregnancy and the puerperium and to identify risk factors for pregnancy-related venous thromboembolism. DESIGN: Cohort study and case-control study. SETTING: London, UK. POPULATION: 395,335 women with live births or pregnancies of 24 or more weeks of gestation between 1988 and 1997. METHODS: Data extraction from the St Mary's Maternity Information System database. Random sample of 5% for case-control study. MAIN OUTCOME MEASURES: Incidence of venous thromboembolism; odds ratios for variables associated with venous thromboembolism. RESULTS: The incidence of venous thromboembolism was 85/100,000 maternities. There were approximately twice as many postpartum as antepartum events. Blood group A, multiple pregnancy, caesarean section, cardiac disease, delivery at gestational age of < 36 weeks, a body mass index of > or = 25, or more and maternal age of 35 or over were all found to increase incidence of venous thromboembolism. CONCLUSIONS: Although venous thromboembolism is the leading cause of maternal deaths in the UK, it is still a rare event. Most of these events are deep vein thromboses occurring in the postpartum period. Antenatally multiple birth is an important risk factor. Postnatally women who have had a caesarean section, premature delivery or history of cardiac disease should be assessed carefully for venous thromboembolism.

Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data.

OBJECTIVE: Minocycline is an antibacterial drug used in the treatment of acne. Concern has been expressed over the possibility of severe adverse reactions to minocycline, including hepatitis. This study set out to identify and characterise reported cases of hepatotoxicity associated with the use of minocycline. METHODS: A systematic review of the literature including a search of computerised databases and analysis of data from the Uppsala Monitoring Centre (WHO Collaborating Centre for International Drug Monitoring) was conducted. The review involved a search for original case reports involving liver damage in people using minocycline. Patients taking minocycline for reasons other than acne or those given intravenous minocycline were excluded. The search strategy involved an enquiry of computerised databases and a search for secondary references. Cases were then classified appropriately. RESULTS: 65 reported cases of hepatitis or liver damage in association with minocycline from either case reports or case series were identified from the literature review. 58% of cases occurred in females and 94% were aged under 40 years. For 20 case reports there was insufficient information to classify the type of event, but for the remaining 45, 2 types of hepatic reaction were recognised: autoimmune hepatitis associated with lupus-like symptoms occurring after a median duration of exposure to minocycline of 365 days in females (n = 20) and 730 days in males (n = 9), hypersensitivity reaction associated with eosinophilia and exfoliative dermatitis occurring within 35 days of therapy (n = 16). Reports to the WHO of hepatic adverse drug reactions associated with minocycline accounted for 6% (493) of all minocycline-related adverse drug reactions (8025). The pattern of distribution in relation to exposure demonstrated 2 groups, similar to that described by the case reports. CONCLUSIONS: Severe cases of minocycline-associated hepatotoxicity appear to be a hypersensitivity reaction and occur within a few weeks of commencing therapy. An autoimmune hepatitis usually presents after exposure to minocycline of a year or more, is more common in women and is sometimes associated with lupus-like symptoms.

The treatment of depression in UK general practice: selective serotonin reuptake inhibitors and tricyclic antidepressants compared.

BACKGROUND: Antidepressants are commonly prescribed by general practitioners as treatment for depression. Controversy exists as to the effectiveness in everyday use of the older tricyclic antidepressants (TCAs) when compared to the newer selective serotonin reuptake inhibitors (SSRIs). AIM: To investigate the patterns of current prescribing of antidepressants for the treatment of depression and compare TCAs with the newer SSRIs. METHOD: The study population was patients attending 151 computerised general practices from throughout the United Kingdom between 1991 and 1996. Patients with new prescriptions for antidepressants and a diagnosis of depression were identified. Age and gender distributions, prescribed doses and drop-out rates were investigated. RESULTS: During the study period 9.8% of patients received a prescription for an antidepressant, there was a 40% increase in the prescribing rate of TCAs and a 460% increase in SSRI prescribing. TCAs were initially prescribed in sub-therapeutic doses. More than 50% of patients ceased taking their antidepressants within 6 weeks of starting treatment. Fluoxetine and paroxetine were more likely to be prescribed for a therapeutic period than were other antidepressants. CONCLUSIONS: General practitioners should prescribe a therapeutic dose of antidepressant for a recognised therapeutic period to ensure that patients with depression receive the most effective treatment.

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.

The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives.

OBJECTIVES: To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates ofidiopathic venous thromboembolism among this population. METHODS: The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives. RESULTS: The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100,000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m2 and over, the association rising dramatically in women with a body mass index of 35 kg/m2 or more; smoking; general ill health; and asthma. CONCLUSION: We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.

Patterns of contraception in UK women with Type 1 diabetes mellitus: a GP database study.

AIM: To establish the patterns of contraceptive prescribing for women aged 15-49 with Type 1 diabetes mellitus (DM) and compare them with the patterns in women without diabetes. METHODS: This was a cross-sectional study using a UK primary care database. RESULTS: Nine hundred and thirty-eight women with a diagnosis of Type 1 DM were identified. A comparison group of women aged 15-49 without diabetes (n = 10000) were randomly selected from the database. Twenty-five per cent of the women with diabetes and 32% without diabetes were prescribed a hormonal contraceptive in 1994. Women with Type 1 DM were more likely to be prescribed a combined oral contraceptive than a progestogen only pill (POP) but were 2.12 (95% CI 1.65-2.72) times more likely to be prescribed a POP than women without diabetes and were less likely to be prescribed a combined pill - odds ratio 0.53 (95% CI 0.44-0.64). The pregnancy rate in women with Type 1 DM over the age of 25 years was lower than for women without diabetes. Women under 25 years with Type 1 DM seemed more likely to record a pregnancy. CONCLUSIONS: Differences between women with Type 1 DM and those without diabetes highlight the variation in the way that GPs and patients evaluate the risks and benefits when deciding on contraception.

PIP: This cross-sectional study using a UK primary care database establishes the patterns of contraceptive prescribing for women aged 15-49 with Type 1 diabetes mellitus (DM) and compares them with the patterns in women without DM. A total of 938 Type 1 DM women were identified and a comparison group of women without diabetes (n = 10,000) were randomly selected from the database. Statistical analysis showed that 25% of the Type 1 DM women and 32% of those without diabetes were prescribed a hormonal contraceptive in 1994. Type 1 DM women were more likely to be prescribed a combined oral contraceptive than a progestogen-only pill (POP). However, they were 2.12 (95% CI, 1.65-2.72) times more likely to be prescribed a POP and less likely to be prescribed a combined pill (odds ratio, 0.53; 95% CI, 1.65-0.64) compared to women without diabetes. In addition, the pregnancy rates in Type 1 DM women over the age of 25 years were lower than in women without diabetes. This finding suggests that Type 1 DM women under age 25 appear more likely to record a pregnancy. In conclusion, differences between Type 1 DM women and those without diabetes highlight the variation in the way that general practitioners and patients evaluate the risks and benefits when deciding on contraception.

Primary care units in A&E departments in North Thames in the 1990s: initial experience and future implications.

BACKGROUND: In 1992, the Tomlinson Report recommended a shift from secondary to primary care, including specific primary care provision in accident and emergency (A&E) departments. Availability of short-term so-called Tomlinson moneys allowed a number of experimental services. A study of the experience of A&E-based staff is reported to assist general practitioners (GPs) and purchasers and identify areas for further research. AIMS: To find the number and scope of primary care facilities in A&E services in North Thames; to find factors encouraging or inhibiting the setting-up of a successful service; to examine the views of a range of A&E staff including GPs, consultants, and nurses; and to suggest directions for more specific research. METHOD: A postal questionnaire was sent to all North Thames A&E departments, and an interview study of staff in one unit was arranged, leading to a questionnaire study of all GPs employed in North Thames primary care services in A&E. This was followed by interviews of staff members in five contrasting primary care units in A&E. RESULTS: By mid-1995, at least 16 of the 33 North Thames A&E departments ran a primary care service. Seven mainly employed GPs, the others employed nurse practitioners (NPs). Problems for GPs included unclear role definition and their non-availability at times of highest patient demand. GPs' reasons for working in A&E sometimes differed from the aims of primary care in an A&E service. Staff interviews revealed differing views about their role and about use of triage protocols. Ethnicity data were being collected, but not yet being used, to improve service to patients. CONCLUSIONS: A number of benefits follow the introduction of primary care practitioners into A&E. Different models have evolved, with a variety of GP and NP staffing arrangements according to local ideas and priorities. There is some confusion over whether these services aim to improve A&E-based care or to divert it to general practice. Cost information is inadequate so far, though the use of GPs has shown the possibility of economy. Appropriate location of services requires clearer identification of costs. This may be possible for the proposed primary care groups.

Oral contraceptives and venous thromboembolic disease. Analyses of the UK General Practice Research Database and the UK Mediplus database.

The results of three independent studies of venous thromboembolic disease (VTE) and oral contraceptives are reviewed together with two further cohort/case-control studies which we conducted using the MediPlus and General Practice Research Database (GPRD) databases. These latter studies jointly involved 395 cases and uniquely examined the association between VTE and individual combined oral contraceptive (COC) formulations. The two studies yielded very similar results. Crude incidence rates for idiopathic VTE of 4.6 and 3.8 were found per 10,000 exposed woman-years (EWY), in the MediPlus and GPRD studies respectively. Incidence rates increased markedly with age, and in both databases the rates amongst users of levonorgestrel products were lower than those amongst users of desogestrel and gestodene products. A case fatality rate of 3% and a mortality rate of 10 per million EWY were estimated. Odds ratios (OR) were calculated for confounding variables and different COC formulations. Both database studies indicated an excess of current smokers and women with high body mass indices amongst cases. There were significantly more cases with asthma in the GPRD study and cases who had been using their COC for less than a year. No statistically significant differences between COC formulations were found in the analyses where controls were matched to cases by practice and year of birth in both the MediPlus and GPRD studies. In the GPRD study we also ran a study where controls were matched by practice and within 5 year age bands. In this study the OR were consistently higher for the newer or 'third generation' products than when controls were matched by year of birth. However only the acne formulation/OC containing cyproterone acetate and 35 microg ethinyloestradiol yielded a significant OR of 2.3. It may be concluded that improvements in prescribing are paramount as the results strongly indicate that overweight women and those who smoke are at a greater risk of VTE. Further study is required to elucidate the possibility that asthma or its treatment may predispose to VTE, alone or in combination with other risk factors. However, neither the MediPlus nor GPRD studies indicate that any one COC formulation poses a greater risk of VTE than another.

Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany.

OBJECTIVE: Three research articles published in late 1995 and early 1996 suggested that oral contraceptives containing either of the newer progestogens (gestodene or desogestrel) could be associated with an increased risk of venous thromboembolism. During the months after the initial publications, the results have been scrutinized with great care and further studies have been published. The findings of 2 recent database studies, 1 in the United Kingdom and 1 in Germany, are presented in this article. PATTERNS OF USE: The average age of users of combined oral contraceptives in Germany was 27 years, compared with 26 years in the United Kingdom. In Germany the use of gestodene-based products was lower than that in the United Kingdom. In the United Kingdom the users of desogestrel with 20 microg ethinyl estradiol (Mercilon) were older than the users of desogestrel with 30 microg ethinyl estradiol (Marvelon). CRUDE INCIDENCE: The crude incidence of venous thromboembolism in the UK study was 4.1 cases/10,000 woman-y exposure to combined oral contraceptives. In Germany it was 4.2 cases/10,000 woman-y. In Germany the rates among users of second-generation combined oral contraceptives were higher than those among users of third-generation products. The reverse was the case in the United Kingdom. In the United Kingdom the crude incidence rates were higher for the 20 microg estrogen desogestrel product than for the 30 microg product. CASE-CONTROL ANALYSIS: The adjusted odds ratios in the UK study did not show significant increases for desogestrel or gestodene compared with levonorgestrel products. There were inconsistencies in the results among centers in the 2 international studies (the World Health Organization and Transnational studies). In both there was a consistent inverse dose-response relationship with estrogen in all centers. CONCLUSION: The limitations of the observational studies are such that the hypothesis that the newer progestogens are more likely to cause venous thromboembolism cannot be proved.

PIP: Research articles published in 1995-96 suggested that oral contraceptives (OCs) containing desogestrel or gestodene are associated with an increased risk of venous thromboembolism. This paper presents the findings of two more recent studies on this association, one from the UK and the other from Germany, both of which were based on general practice computer-generated clinical databases. The median age of OC users was 26 years in the UK study and 27 years in the German study. The crude incidence of venous thromboembolism per 10,000 woman-years of OC exposure was 4.1 cases in the UK study and 4.2 cases in Germany. In Germany, this rate was higher among users of second-generation OCs (4.03 cases per 10,000 woman-years) than third-generation OCs (3.95 cases per 10,000 woman-years). In the UK, the reverse pattern was found: 4.96 and 3.10 cases per 10,000 woman-years for third- and second-generation products, respectively. Moreover, crude incidence rates were higher for the 20 mcg estrogen-desogestrel formulation than for the OC containing desogestrel and 30 mcg of estrogen--a biologically implausible finding. The adjusted odds ratios in the UK study did not show any significant increases in venous thromboembolism risk for desogestrel or gestodene compared with levonorgestrel. Overall, these findings fail to provide support for the hypothesis that the newer progestogens are more likely to cause venous thromboembolism.

Population-based study of risk of venous thromboembolism associated with various oral contraceptives.

BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding.

PIP: Four studies published since December 1995 have reported an increased risk of venous thromboembolism (VTE) in women using oral contraceptives (OCs) containing the third-generation progestogens gestodene and desogestrel compared to users of OCs containing second-generation progestogens. The results of these studies could have been compromised, however, by bias and confounding. To reassess this association with a more rigorous study design, computerized medical records from 143 general practices in the UK of about 540,000 women born from 1941 to 1981 were reviewed and 83 cases of deep-vein thrombosis, venous thrombosis not otherwise specified, and pulmonary embolus (all treated with an anticoagulant) were identified. Two women were using a progestogen-only OC. Of the 83 VTE cases associated with combined OC use, 43 were diagnosed as deep-vein thrombosis, 35 as pulmonary thrombosis, and 5 as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation OCs. After exact age matching of cases and controls, the odds ratio of VTE in users of third-generation compared to second-generation OCs was 1.68 (95%, confidence interval, 1.04-2.75). Logistic regression revealed no significant difference in VTE risk between users of the 2 groups of OCs. Using all second-generation OCs as the reference, the VTE risk was higher for third-generation OCs containing desogestrel and 20 grams of ethinyl estradiol than for those containing desogestrel or gestodene and 30 grams of ethinyl estradiol--an implausible finding presumed to reflect preferential prescribing of the former OCs to older women. The previously reported increased VTE risk associated with third-generation OCs likely reflects residual confounding by age. Exact age-matching is recommended for all future studies to ensure that controls are representative of the population from which cases are drawn.