Martin Vessey

Risk of venous thromboembolism in users of hormone replacement therapy

BACKGROUND The association between current use of oral contraceptives and increased risk of venous thromboembolism (VTE) has been firmly established. Although data-sheets for hormone replacement therapy (HRT) carry similar warnings as regards VTE, evidence of an association is inconclusive. We carried out a hospital-based case-control study to investigate whether current use of HRT is associated with VTE. METHODS We screened all women aged 45-64 years admitted to hospitals in the area of the Oxford Regional Health Authority with a suspected diagnosis of VTE between February, 1993, and December, 1994. We recruited 81 cases of idiopathic VTE and 146 hospital controls with disorders of eyes, skin, ears, respiratory and alimentary tracts, kidneys, bones, and joints, and trauma; controls were matched to cases for age-group and date and district of admission. To increase the study power, an additional 22 cases of idiopathic VTE and 32 hospital controls admitted before February, 1993, were recruited retrospectively. Participants were questioned about medical and gynaecological history, use of oral contraceptives and HRT, use of other drugs within the previous 3 months, and lifestyle and socioeconomic characteristics. Detailed diagnostic data were extracted from the notes of eligible cases. Matched analyses, adjusted for body-mass Index, socioeconomic group, and history of varicose veins, were undertaken by conditional logistic regression. FINDINGS 44 (42.7%) cases and 44 (24.7%) controls were current users of HRT. The adjusted odds ratio for VTE in current users of HRT compared with non-users (never-users and past users combined) was 3.5 (95% CI 1.8-7.0; p < 0.001). No association was found with past use, and risk appeared to be highest among short-term current users (adjusted likelihood ratio test of trend in odds ratios across different durations of current use, p = 0.011). INTERPRETATION Current HRT use is associated with risk of VTE. The increased risk may be concentrated in new users. The number of extra cases appears to be only about one in 5000 users per year. These findings need to be weighed against the probable benefits of long-term treatment, including reductions in risks of osteoporotic fracture and coronary heart disease, and the probable modest increase in risk of breast cancer.

Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of peptic ulcer complications, but it is not clear whether some drugs are more likely than others to cause such complications. We compared previous use of NSAIDs in 1144 patients aged 60 and older admitted to hospitals in five large cities with peptic ulcer bleeding and in 1126 hospital controls and 989 community controls matched for age and sex. Peptic ulcer bleeding was strongly associated with use of non-aspirin NSAIDs of any type during the 3 months before admission (411 cases, 351 controls; odds ratio 4.5 [95% CI 3.6 to 5.6]). The odds ratios for peptic ulcer bleeding were lowest for ibuprofen (2.0 [1.4-2.8]) and diclofenac (4.2 [2.6-6.8]), and intermediate for indomethacin, naproxen, and piroxicam (11.3 [6.3-20.3], 9.1 [5.5-15.1], and 13.7 [7.1-26.3]). Azapropazone and ketoprofen carried the highest risks (31.5 [10.3-96.9] and 23.7 [7.6-74.2]). Risks also increased with drug dose (low dose 2.5 [1.7-3.8], intermediate 4.5 [3.3-6.0], and high 8.6 [5.8-12.6]) for all drugs combined. Appropriate clinical strategies could prevent many episodes of peptic ulcer bleeding: NSAIDs should be used only in patients who do not respond to other analgesics; the lowest possible doses should be used; and the least toxic NSAIDs should be selected.

Epidemiology of genital prolapse: observations from the Oxford Family Planning Association study

Objective To explore the epidemiology of uterovaginal and post‐hysterectomy prolapse.

Prophylactic aspirin and risk of peptic ulcer bleeding

Abstract Objective: To determine the risks of hospitalisation for bleeding peptic ulcer with the current prophylactic aspirin regimens of 300 mg daily or less. Design: A case-control study with hospital and community controls. Setting: Hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth. Subjects: 1121 patients with gastric or duodenal ulcer bleeding matched with hospital and community controls. Results: 144 (12.8%) cases had been regular users of aspirin (taken at least five days a week for at least the previous month) compared with 101 (9.0%) hospital and 77 (7.8%) community controls. Odds ratios were raised for all doses of aspirin taken, whether compared with hospital or community controls (compared with combined controls: 75 mg, 2.3 (95% confidence interval 1.2 to 4.4); 150 mg, 3.2 (1.7 to 6.5); 300 mg, 3.9 (2.5 to 6.3)). Results were not explained by confounding influences of age, sex, prior ulcer history or dyspepsia, or concurrent non-aspirin non-steroidal anti-inflammatory drug use. Risks seemed particularly high in patients who took non-aspirin non-steroidal anti-inflammatory drugs concurrently. Conclusion: No conventionally used prophylactic aspirin regimen seems free of the risk of peptic ulcer complications. Key messages Key messages This finding applies to doses in common use of 75, 150, and 300 mg daily Despite these results, overall benefits of treatment are likely considerably to outweigh possible risks

The epidemiology of hysterectomy: findings in a large cohort study

Objective To examine patterns of hysterectomy in the Oxford‐Family Planning Association (Oxford‐FPA) study in relation to age, parity, social class and calendar period (–1974, 1975–79. 1980–84, 1985–89).

Polycystic ovaries and associated clinical and biochemical features in young women

To determine the prevalence of polycystic ovaries as identified by ultrasound in a group of young, postmenarcheal women in the normal population, and to investigate how polycystic ovaries are related to the spectrum of clinical and biochemical symptoms associated with the polycystic ovary syndrome (PCOS).

Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report.

The results of a previous study of the use of oral contraceptives by married women discharged from hospital with a diagnosis of thromboembolic disease in the years 1964–6 were reported by us last year. The present paper adds results relating to patients discharged during 1967 and a few data, that could not be sought previously, for patients discharged with cerebral or coronary thrombosis from three of the hospitals in the earlier period. Of 84 patients with deep-vein thrombosis or pulmonary embolism 42 (50%) had used oral contraceptives during the month preceding the onset of their illness, while only 23 of the 168 controls (14%) had done so. No differences in risk were found either for the types of preparation or for the duration of use. After allowance for age and height, the patients with venous thromboembolism were about 10 lb. (4,535 g.) heavier than the control patients, irrespective of whether they were using oral contraceptives or not. No appreciable difference was found between the smoking habits of patients with and without venous thromboembolism treated during 1967, nor between women who were using oral contraceptives and those who were not. The trend in hospital admissions for venous thromboembolism with time corresponded to the trend in the use of oral contraceptives, and there was no evidence to suggest that the number of admissions was affected by publicity about the risk of using the preparations. Of 19 patients with cerebral thrombosis 11 (58%) had been using oral contraceptives, compared with an expected figure of 3.5 from the experience of the control subjects. All the published data (clinical, angiographic, and post-mortem) show that the thrombosis affects the cerebral arteries rather than the cerebral veins. Of 17 patients with coronary thrombosis 2 (12%) had been using oral contraceptives, compared with an expected figure of 2.1. The patients with coronary thrombosis smoked more than the control patients and were, on average, 8.3 lb. (3,765 g.) heavier than control women of the same age and height. The new evidence strengthens the belief that oral contraceptives are a cause of venous thromboembolism and cerebral thrombosis but does not indicate that they are a cause of coronary thrombosis.

A Long-term follow-up study of women using different methods of contraception— an interim report

In 1968, a prospective study was started in collaboration with the Family Planning Association to try to provide a balanced view of the beneficial and harmful effects of different methods of contraception. This investigation is now in progress at seventeen clinics and over 17,000 women are under observation. At the time of recruitment, all these women were married white British subjects, aged 25–39 years, who voluntarily agreed to participate. Fifty-six per cent were using oral contraceptives, 25% were using a diaphragm and 19% were using an intrauterine device (IUD). During follow-up each woman is questioned at return visits to the clinic and a record of pregnancies and their outcome, hospital referrals (inpatient or outpatient), changes in contraceptive methods and the results of cervical smears, is accumulated. Women who default are sent a postal questionnaire and, if this is not returned, are telephoned or visited in their homes to collect the necessary information. So far, data obtained during 56,000 woman-years of observation are available for analysis. Follow-up has been maintained with an annual lapse rate of about 0.3%due to withdrawal of co-operation or loss of contact; adherence to the method of contraception in use at recruitment has been reasonably good, and the reporting of pregnancies and hospital admissions appears to have been both reliable and unbiased. The present data include only 24 deaths, so the mortality associated with different contraceptive methods cannot yet be estimated. With regard to morbidity, however, our preliminary results closely resemble those obtained in the prospective study carried out by the Royal College of General Practitioners (1974) and in the principal retrospective studies carried out in Britain and the United States. Women who used oral contraceptives at the start of the study experienced a deficiency of hospital referrals for cancer, benign lesions of the breast, menstrual disorders other than amenorrhoea, duodenal ulcer, and retention cysts of the ovary; they showed an excess of referrals for cerebrovascular disease, cervical erosion, skin disorders, self-poisoning, migraine, venous thrombosis and embolism, hayfever, gallbladder disease, amenorrhoea, and sterility. Women who used a diaphragm showed a deficiency of hospital referrals for carcinoma-in-situ and dysplastic lesions of the cervix uteri and accidental injury; and an excess of referrals for haemorrhoids and cystitis. Women who used an IUD experienced an excess of hospital referrals for anaemia, varicose veins and salpingitis. About half of these differences (12 out of 23) were predicted from other studies while some suggestive evidence already existed for a further five. Of the remaining six, some probably reflect the influence of selective factors or chance. Multiple pregnancies, stillbirths, malformations, the sex ratio and birthweight showed no consistent relationship to method of contraception. The outcome of unplanned pregnancies occurring in women using an IUD, however, was remarkably unfavourable both in terms of ectopic gestation and miscarriage. Clear evidence was found of impairment of fertility after discontinuation of oral contraceptives. Whether this is likely to lead to permanent sterility in some women is uncertain. The study has provided data on the efficacy of a wide variety of contraceptive methods. In general the failure rates are in keeping with those obtained in other large-scale studies, save that those for the diaphragm and the sheath are much lower than those usually quoted. The available evidence does not yet allow a final balance to be struck between the benefits and risks associated with the new methods of contraception that have become widely used during the last two decades. It seems clear, however, that there are no material risks associated with the use of the diaphragm apart from the risk of pregnancy and that there may be some unintended benefits.

Myocardial infarction in young women with special reference to oral contraceptive practice.

Sixty-three women discharged from hospital with a diagnosis of myocardial infarction and 189 control patients were studied. All were under 45 years of age at the time of admission. Current oral contraceptive use, heavy cigarette smoking, treated hypertension and diabetes, pre-eclamptic toxaemia, and obesity were all reported by, and type II hyperlipoproteinaemia was found more often in, patients with myocardial infarction than their controls. The relationship between myocardial infarction and oral contraceptives could not be explained in terms of an association between the use of these preparations and the other factors. The combined effect of the risk factors was clearly synergistic.

Routine follow up of breast cancer in primary care: randomised trial.

Abstract Objective: To assess the effect on time to diagnosis of recurrence and on quality of life of transferring primary responsibility for follow up of women with breast cancer in remission from hospital to general practice. Design: Randomised controlled trial with 18 month follow up in which women received routine follow up either in hospital or in general practice. Subjects and setting: 296 women with breast cancer in remission receiving regular follow up care at district general hospitals in England. Main outcome measures: Time between first presentation of symptoms to confirmation of recurrence; quality of life measured by specific dimensions of the SF-36 schedule, the EORTC symptom scale, and hospital anxiety and depression scale. Results: Most recurrences (18/26, 69%) presented as interval events, and almost half (7/16, 44%) of the recurrences in the hospital group presented first to general practice. The median time to hospital confirmation of recurrence was 21 days in the hospital group (range 1-376 days) and 22 days in the general practice group (range 4-64). The differences between groups in the change in SF-36 mean scores from baseline were small: -1.8 (95% confidence interval -7.2 to 3.5) for social functioning, 0.5 (-4.1 to 5.1) for mental health, and 0.6 (-3.6 to 4.8) for general health perception. The change from baseline in the mean depression score was higher in the general practice group at the mid-trial assessment (difference 0.6, 0.1 to 1.2) but there was no significant difference between groups in the anxiety score or the EORTC scales. Conclusion: General practice follow up of women with breast cancer in remission is not associated with increase in time to diagnosis, increase in anxiety, or deterioration in health related quality of life. Most recurrences are detected by women as interval events and present to the general practitioner, irrespective of continuing hospital follow up. Key messages Broadly, the goals of follow up are to detect recurrence, detect new contralateral primaries, and provide psychosocial support For women who are free of disease, general prac- tice follow up was not associated with increased time to diagnosis of recurrence or deterioration in health related quality of life