Unblinding of trial participants to their treatment allocation: lessons from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: The gold standard clinical trial design is the double-blind, randomized, controlled trial. No standard practice exists for the "unblinding" of trial participants and no legal obligation is placed on investigators to inform participants of their treatment allocation or study results at the end of a trial. Here we document our experiences of unblinding the 2520 Scottish participants in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). METHODS: The objectives of the PROSPER unblinding process were to provide all study participants with their study medication status and on-trial cholesterol levels and to respect the rights of participants not to be unblinded. It was considered imperative by the study executive that the blind was maintained until the presentation and publication of the results. Staff therefore remained "blinded" throughout the unblinding process. Inappropriate contact with the PROSPER participants was avoided by confirming their current vital status and health status. RESULTS: To coincide with the presentation of the PROSPER results, all participants, for whom it was deemed appropriate, were sent a summary of the results and were offered the opportunity to be advised of their treatment allocation and on-trial lipid profiles. The majority of participants opted for telephone unblinding. All primary care physicians who had patients randomised to the study were also sent a summary of the study results and sealed documents detailing the treatment allocation and lipid profiles for each patient. Relocated patients were traced and the information forwarded to their new primary care physicians. CONCLUSION: The dissemination of study results and treatment allocation to study participants is an integral part of the research process and should be included in the design of any clinical trial.

Statin therapy in the elderly.

PURPOSE OF REVIEW: The clinical efficacy and safety of statin therapy have been well established from a series of large-scale, randomized controlled trials. These trials, however, have predominantly recruited patients under the age of 70 years. As a consequence, the use of statins in older patients has remained controversial. RECENT FINDINGS: The results of the first trial to look exclusively at the elderly--the Prospective Study of Pravastatin in the Elderly at Risk--have added enormously to our understanding of the use of statins in the elderly. These findings, together with those from the large elderly cohort within the Heart Protection Study and the smaller elderly subgroups within the other major statin trials, have forced us to re-evaluate any systematic exclusion of elderly patients from statin therapy. SUMMARY: The collective evidence now strongly supports the use of statins in the at-risk elderly population.

Understanding why older people participate in clinical trials: the experience of the Scottish PROSPER participants.

BACKGROUND: over the next 20 years it is anticipated that there will be a significant increase in those aged 75 and over, and a consequent increase in cardiovascular disease, cancer and chronic illness. As this shift takes effect, there will be an increased need for treatment strategies that are of known benefit to this age group and a consequent rise in demand for clinical trials that are conducted specifically with the older population. Because factors that motivate older individuals to participate in clinical trials may differ from those that influence younger adults, it is important to evaluate the strategies used to encourage recruitment and retention and to determine how appropriate these are. AIM: evaluation of the reasons why subjects agree to participate in a controlled clinical trial of vascular disease prevention and the strategies used to improve compliance and protocol adherence. SETTING: Scotland. SUBJECTS: 2,520 Prospective Study of Pravastatin in the Elderly at Risk participants, aged 70-82 with either pre-existing vascular disease or at least one major vascular risk factor (hypertension, cigarette smoking, or diabetes mellitus). DESIGN OF STUDY: two-stage iterative survey. Stage I was exploratory. RESULTS: curiosity, or an interest in finding out more about the study, 'a desire to support research', and anticipated personal benefits, such as health screening, were the most important motivators for generating initial interest in the trial. Ongoing health monitoring was the most important recruitment and retention motivator (P = 0.001). CONCLUSIONS: curiosity, self interest and altruism may act as motivators at different points in the study time-line. However, fostering positive relationships between staff and recruits, and keeping recruits informed about the progress of the study are likely to maximise the retention of older subjects to long-term trials.

Closing out a large clinical trial: lessons from the prospective study of pravastatin in the elderly at risk (PROSPER).

Relatively little has been written about the practicalities of the closeout of large, multi-centre clinical trials, but this aspect of trial conduct and design is both important and requires careful planning in order to be accomplished in a timely and orderly fashion. Here, we document our recent experiences of closing down the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This five-year study with over 5800 subjects was closed down and published in 2002. We describe the methods used to ensure the speedy progression from the start of the closeout period through data lock to publication and presentation of the results. We discuss the strategic planning of all aspects of the closeout process, the training of staff for final visits, the methods used to follow-up all study participants including those used in dealing with "difficult to contact" and defaulted patients, and the strategies employed to ensure that study participants were left with positive feelings about the study. We also detail the methods employed to expedite the throughput of study paperwork and endpoints and the cleaning of data in preparation for data lock and subsequent publication and presentation of the results. Based on our experiences we summarize the most important aspects of closeout design and make recommendations for future studies, the most important of which is that a well-planned and well-managed closeout is a key feature of any large scale clinical trial and a coherent and practicable closeout strategy should be an integral part of the design.

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.