European active surveillance study of women taking HRT (EURAS-HRT): study protocol [NCT00214903]

BACKGROUND: The post marketing safety surveillance program for a drug containing a new chemical entity should assess both, the safety outcomes that relate specifically to the targeted population, as well as those that could potentially be related to special pharmacological characteristics of the drug. Active safety surveillance using valid epidemiological study designs has been proven to be a pertinent and reliable method to approach this endeavor. METHODS/DESIGN: The primary objective of the study is to compare incidence rates of serious adverse events in users of all types of newly prescribed oral HRT products. This active surveillance study will assess pertinent cardiovascular outcomes - in particular venous and arterial thromboembolism - and other serious adverse events (SAEs) in new HRT users over a period of several years. One product under surveillance is Angeliq(®), which contains the novel progestagen drospirenone (DRSP) combined with estradiol. In addition, all other oral combined HRT products with a novel progestagen or estrogen that will be newly marketed during the study period will be studied. These new HRT products will be compared with established HRT products. The combined cohort will include at least 30,000 women recruited in several European countries. At least 90,000 years of observation are expected from the field work which started in early 2002 and will end around 2008. The participating women will complete a baseline survey using a self-administered questionnaire to describe the baseline risk. After 6 months, 12 months, and then on an annual basis, they will fill out a questionnaire in which they record complaints and events during the use of the prescribed HRTs. All adverse outcomes occurring during the observational period will be evaluated. DISCUSSION: A complete lifetime medical history, individually validated SAEs over time, and a low loss to follow-up rate are essential for a robust safety assessment. Therefore, the lifetime history of diseases and relevant medications will be documented. Reported SAEs will be validated and analyzed. A four level, multi-faceted follow-up process was established to ensure low loss to follow-up rates (e.g., 3–5% after three years of follow up). Multivariate methods will be used to adjust for confounding

Expanding the perspective of translational medicine: the value of observational data

In 2003, the Journal of Translational Medicine was launched to foster the publication of high quality research in both "bench-to-bedside" as well as ex vivo human observation. In spite of the success of several large-scale observational studies, e.g. Framingham Heart Study, the opportunity to expand upon the ex vivo human observation has remained limited within the field of translational medicine. We believe that this presents a significant opportunity that merits consideration in both the planning and analysis of large scale observational studies and can contribute greatly to expanding our approaches in translational medicin

Colon cancer risk and different HRT formulations: a case-control study

<p>Abstract</p> <p>Background</p> <p>Most studies have found no increased risk of colon cancer associated with hormone replacement therapy (HRT), or even a decreased risk. But information about the effects of different HRT preparations is lacking.</p> <p>Methods</p> <p>A case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched to each case of colon cancer. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to get an impression of the risk associated with different estrogens and progestins.</p> <p>Results</p> <p>A total of 354 cases of colon cancer were compared with 1422 matched controls. The adjusted overall risk estimate for colon cancer (ColC) associated with ever-use of HRT was 0.97 (0.71 – 1.32). No clinically relevant trends for ColC risk were observed with increasing duration of HRT use, or increasing time since first or last HRT use in aggregate.</p> <p>Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT preparation groups (estrogens and progestins) were too small for conclusions. Nevertheless, if the ColC risk estimates are taken at face value, most seemed to be reduced compared with never-use of HRT, but did not vary much across HRT formulation subgroups. In particular, no substantial difference in ColC risk was observed between HRT-containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe.</p> <p>Conclusion</p> <p>Ever-use of HRT was not associated with an increased risk of colon cancer. In contrary, most risk estimates pointed non-significantly toward a lower ColC risk in HRT ever user. They did not vary markedly among different HRT formulations (estrogens, progestins). However, the small numbers and the overlapping nature of the subgroups suggest cautious interpretation.</p

Seminars may increase recruitment to randomised controlled trials: lessons learned from WISDOM

Background: Recruiting patients to large randomised controlled trials (RCTs) in the primary care setting can be challenging. Research teams need to identify and utilise strategies that both maximise the efficiency of recruitment and minimise the burden on general practitioners. Purpose: To describe our methods for identifying, approaching and recruiting female patients aged 50–69 years to a long-term double-blind RCT of hormone therapy (HT) – the Women's International Study of long Duration Oestrogen after Menopause (WISDOM). The effectiveness of conducting group seminars with patients prior to one-to-one screening is discussed. Methods: Female patients aged between 50 and 69 years were sent letters from participating general practitioners in Adelaide inviting them to participate in WISDOM and attend an initial seminar providing information about HT and the trial prior to a screening interview with a trial nurse. Recruitment rates for those who did or did not attend group seminars were compared. Results: Women who attended a group seminar conducted by the research team were twice as likely to attend an initial screening visit and enrol to participate in WISDOM than women who did not attend a seminar (p &lt; 0.001). In addition, it was estimated that the time required to randomise a woman in the trial, and the number and duration of telephone calls to screen out uninterested women, was reduced for the seminar group. Conclusion: Conducting group seminars with potential participants may be a useful strategy for maximising recruitment from general practice, by increasing patient information and reducing a research team's workload.Bronwen J. Paine, Nigel P. Stocks and Alastair H. MacLenna

Designing theoretically-informed implementation interventions: Fine in theory, but evidence of effectiveness in practice is needed

The Improved Clinical Effectiveness through Behavioural Research Group (ICEBeRG) authors assert that a key weakness in implementation research is the unknown applicability of a given intervention outside its original site and problem, and suggest that use of explicit theory offers an effective solution. This assertion is problematic for three primary reasons. First, the presence of an underlying theory does not necessarily ease the task of judging the applicability of a piece of empirical evidence. Second, it is not clear how to translate theory reliably into intervention design, which undoubtedly involves the diluting effect of "common sense." Thirdly, there are many theories, formal and informal, and it is not clear why any one should be given primacy. To determine whether explicitly theory-based interventions are, on average, more effective than those based on implicit theories, pragmatic trials are needed. Until empirical evidence is available showing the superiority of theory-based interventions, the use of theory should not be used as a basis for assessing the value of implementation studies by research funders, ethics committees, editors or policy decision makers

A perfect correlate does not a surrogate make

BACKGROUND: There is common belief among some medical researchers that if a potential surrogate endpoint is highly correlated with a true endpoint, then a positive (or negative) difference in potential surrogate endpoints between randomization groups would imply a positive (or negative) difference in unobserved true endpoints between randomization groups. We investigate this belief when the potential surrogate and unobserved true endpoints are perfectly correlated within each randomization group. METHODS: We use a graphical approach. The vertical axis is the unobserved true endpoint and the horizontal axis is the potential surrogate endpoint. Perfect correlation within each randomization group implies that, for each randomization group, potential surrogate and true endpoints are related by a straight line. In this scenario the investigator does not know the slopes or intercepts. We consider a plausible example where the slope of the line is higher for the experimental group than for the control group. RESULTS: In our example with unknown lines, a decrease in mean potential surrogate endpoints from control to experimental groups corresponds to an increase in mean true endpoint from control to experimental groups. Thus the potential surrogate endpoints give the wrong inference. Similar results hold for binary potential surrogate and true outcomes (although the notion of correlation does not apply). The potential surrogate endpointwould give the correct inference if either (i) the unknown lines for the two group coincided, which means that the distribution of true endpoint conditional on potential surrogate endpoint does not depend on treatment group, which is called the Prentice Criterion or (ii) if one could accurately predict the lines based on data from prior studies. CONCLUSION: Perfect correlation between potential surrogate and unobserved true outcomes within randomized groups does not guarantee correct inference based on a potential surrogate endpoint. Even in early phase trials, investigators should not base conclusions on potential surrogate endpoints in which the only validation is high correlation with the true endpoint within a group

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.

CONTEXT:Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE:To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN:Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS:Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES:The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS:On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS:Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

Hormone therapy after the Women's Health Initiative: a qualitative study

BACKGROUND: Publication of results from the Women's Health Initiative study in July 2002 was a landmark event in biomedical science related to postmenopausal women. The purpose of this study was to describe the impact of new hormone therapy recommendations on patients' attitudes and decision-making in a primary care practice. METHODS: A questionnaire including structured and open-ended questions was administered in a family practice office waiting room from August through October 2003. Rationale for taking or not taking hormone therapy was specifically sought. Women 50–70 years old attending for office visits were invited to participate. Data were analyzed qualitatively and with descriptive statistics. Chart review provided medication use rates for the entire practice cohort of which the sample was a subset. RESULTS: Respondents (n = 127) were predominantly white and well educated, and were taking hormone therapy at a higher rate (38%) than the overall rate (26%) for women of the same age range in this practice. Belief patterns about hormone therapy were, in order of frequency, 'use is risky', 'vindication or prior beliefs', 'benefit to me outweighs risk', and 'unaware of new recommendations'. Twenty-eight out of 78 women continued hormones use after July 2002. Of 50 women who initially stopped hormone therapy after July 2002, 12 resumed use. Women who had stopped hormone therapy were a highly symptomatic group. Responses with emotional overtones such as worry, confusion, anger, and grief were common. CONCLUSION: Strategies for decision support about hormone therapy should explicitly take into account women's preferences about symptom relief and the trade-offs among relevant risks. Some women may need emotional support during transitions in hormone therapy use