Madge R Vickers

Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women

Objective To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy). Design Multicentre, randomised, placebo controlled, double blind trial. Setting General practices in UK (384), Australia (91), and New Zealand (24). Participants Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56 583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22 300) started treatment. Interventions Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned. Main outcome measures Primary outcomes: major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life. Results The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the womens health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences. Conclusions Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the womens health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different. Trial registration Current Controlled Trials ISRCTN 63718836

Health related quality of life after combined hormone replacement therapy: randomised controlled trial

Objective To assess the effect of combined hormone replacement therapy (HRT) on health related quality of life. Design Randomised placebo controlled double blind trial. Setting General practices in United Kingdom (384), Australia (94), and New Zealand (24). Participants Postmenopausal women aged 50-69 at randomisation; 3721 women with a uterus were randomised to combined oestrogen and progestogen (n=1862) or placebo (n=1859). Data on health related quality of life at one year were available from 1043 and 1087 women, respectively. Interventions Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year. Main outcome measures Health related quality of life and psychological wellbeing as measured by the women’s health questionnaire. Changes in emotional and physical menopausal symptoms as measured by a symptoms questionnaire and depression by the Centre for Epidemiological Studies depression scale (CES-D). Overall health related quality of life and overall quality of life as measured by the European quality of life instrument (EuroQol) and visual analogue scale, respectively. Results After one year small but significant improvements were observed in three of nine components of the women’s health questionnaire for those taking combined HRT compared with those taking placebo: vasomotor symptoms (P<0.001), sexual functioning (P<0.001), and sleep problems (P<0.001). Significantly fewer women in the combined HRT group reported hot flushes (P<0.001), night sweats (P<0.001), aching joints and muscles (P=0.001), insomnia (P<0.001), and vaginal dryness (P<0.001) than in the placebo group, but greater proportions reported breast tenderness (P<0.001) or vaginal discharge (P<0.001). Hot flushes were experienced in the combined HRT and placebo groups by 30% and 29% at trial entry and 9% and 25% at one year, respectively. No significant differences in other menopausal symptoms, depression, or overall quality of life were observed at one year. Conclusions Combined HRT started many years after the menopause can improve health related quality of life. Trial registration ISRCTN 63718836.

Regular inhaled salbutamol and asthma control: the TRUST randomised trial

BACKGROUND Previous work has suggested that the long-term regular use of inhaled beta2-agonist bronchodilators might lead to a deterioration in asthma control. The aim of TRUST (The Regular Use of Salbutamol Trial) was to study the effects of regular use of inhaled salbutamol, the most widely prescribed bronchodilator in the UK, on the control of asthma. METHODS A randomised, double-blind, placebo-controlled trial was undertaken in 983 patients with asthma being treated at least twice a week with short-acting beta2-agonist, alone or in combination with inhaled steroids (2 mg or less) daily. Patients were aged 18 years and over and were recruited from 115 general practices in the UK. 90% (881) of the patients used inhaled corticosteroid therapy, and all patients continued to use their usual inhaled beta2-agonist for symptomatic relief. Patients were randomised to receive 400 microg salbutamol or matched placebo via a Diskhaler four times per day for 12 months. The primary outcome measure was rate of exacerbations of asthma, with criteria based on data from diary cards completed daily by each patient, treatment with additional corticosteroids, or both. FINDINGS There were no differences in the annual rate, timing, or duration of exacerbations between the two groups. The mean morning peak expiratory flow was similar for the two groups. The mean evening peak expiratory flow (p<0.001) and the diurnal variation (p<0.001) were greater, and the use of rescue bronchodilator was less (p<0.001), in the group receiving regular salbutamol. INTERPRETATION There was no evidence that regular use of inhaled salbutamol 400 microg four times daily for a year increased the exacerbation rate of asthma in the population studied.

Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study

Objective To determine whether older patients with chronic knee pain should be advised to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs). Design Randomised controlled trial and patient preference study. Setting 26 general practices. Participants People aged ≥50 with knee pain: 282 in randomised trial and 303 in preference study. Interventions Advice to use topical or oral ibuprofen. Primary outcome measures WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, major and minor adverse effects. Results Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval −2 to 6); in the preference study, it was one point (−4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference −17% to −2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 µmol/l to 6.5 µmol/l); and more participants changed treatments because of adverse effects (16% v 1%, −16% to −5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness. Conclusions Advice to use oral or topical preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs. Trial registration ISRCTN 79353052.

The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial

BackgroundAt the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Womens Health Initiative trial was designed, funded and started in the US.DesignRandomised, placebo, controlled, trial.MethodsThe trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease.ResultsThe trial was prematurely closed during recruitment following publication of early results from the Womens Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years.DiscussionThe WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding.

Cumulative flying time and risk of venous thromboembolism

The risk of venous thromboembolism (VTE) associated with cumulative flying time remains uncertain. In a case–control study in general practices throughout the UK, participants comprised 550 VTE cases identified from practice records and 1971 age‐ and gender‐matched controls. Participants returned identical questionnaires asking for information including air travel details. Compared to not flying, cumulative flying time >12 h within the previous 4 weeks was associated with a threefold increase in the risk of VTE [odds ratio (OR) 2·75, 95% confidence interval (CI), 1·44–5·28]. Those who had flown >4 h in a single leg in the previous 4 weeks had twice the risk of VTE (OR 2·20, 95% CI, 1·29–3·73). These risks were no longer evident by 12 weeks and were similar to those of day‐case or minor surgery (OR 5·35, 95% CI, 2·15–13·33). Equivalent risks for moderate and high‐risk surgery were over 30‐fold (OR 36·57, 95% CI, 13·05–102·52) and 140‐fold (OR 141·71, 95% CI, 19·38–1036·01) respectively. The temporary nature of the association of cumulative and long‐haul air travel with VTE suggests a causal relationship. The risks of VTE in those with a higher baseline risk due to surgery, previous VTE or obesity are further increased by air travel.