The importance and challenge of recruitment for peripheral artery disease randomized clinical trials

People with lower extremity peripheral artery disease (PAD) have higher rates of cardiovascular events, greater functional impairment, and higher rates of functional decline and mobility loss compared to people without PAD.^1–4 As improved medical therapy has reduced cardiovascular events, PAD patients are living longer with functional impairment and disability. Yet non-invasive therapies to improve walking performance and prevent mobility loss remain largely unavailable or ineffective for most patients with PAD. No new medications have been approved for treating PAD-related walking impairment in more than 15 years, even as the number of people living with PAD-related walking impairment has increased. ⁵ A recent report concluded that medical therapies have not kept pace with the growing burden of disability in the US or worldwide. ⁶ New therapies are urgently needed to improve walking performance and prevent functional decline in patients with PAD.

Identifying new therapies for PAD requires successfully testing novel interventions in adequately statistically powered randomized clinical trials. Yet recruiting and enrolling patients with PAD into randomized clinical trials is challenging.^7–11 For example, the Exercise vs Angioplasty in Claudication Trial (EXACT), a multi-centered clinical trial from the United Kingdom, designed to compare the ability of angioplasty to improve walking performance in PAD as compared to supervised exercise and usual care, was terminated early due to slow enrollment. ⁸ After screening 372 patients referred from primary care practices, only 23 (6%) were randomized, representing 10% of the total number needed for the trial. Reasons for the poor recruitment in EXACT included that many potential participants preferred a specific treatment and were not interested in randomization. In addition, a large number of exclusion criteria resulted in many ineligible participants. The Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study, a multi-centered United States clinical trial designed to determine the relative efficacy of aorto-iliac stenting plus angioplasty versus supervised exercise versus optimal medical therapy alone randomized just 111 of the originally targeted 252 participants. ⁹

Recruitment challenges are not unique to clinical trials of PAD. Bernardez-Pereira et al. searched ClinicalTrials.gov from February 2000 to January 2013 to collect information about randomized clinical trials of cardiovascular disease that were terminated early. ¹¹ Of 6279 cardiovascular clinical trials identified, 684 (10.9%) were stopped early. The most common reason for early termination was lower than anticipated recruitment rates (278 trials, comprising 53.6% of those terminated early). Even in clinical trials that are not terminated early, slow recruitment may result in insufficient sample sizes to adequately test study hypotheses.

In this issue of Vascular Medicine, Love et al. report their experience recruiting African American participants with PAD for a randomized clinical trial testing whether motivational interviewing successfully increases home-based walking exercise. ¹² The study was initiated in Wichita, Kansas. Because of slower than anticipated recruitment rates, recruitment was extended to include Kansas City (both Kansas and Missouri). Over a 3.5-year period, 174 African American participants with PAD were randomized, achieving 85% of the original recruitment goal of 204 randomized participants. Three thousand five hundred and eleven telephone screening calls were completed in order to randomize the 174 participants. These 3511 telephone screening calls were generated by more than eight recruitment methods conducted in community settings. Mailed recruitment brochures and television advertisements together accounted for most of the telephone screening calls. In Wichita, 59.3% of all telephone screening calls, and in Kansas City 82.5% of all telephone screening calls, were initiated by individuals who learned of the study via direct mailings or television advertisements.

The number of telephone calls received for a particular recruitment source is less important than the number of participants randomized from a particular recruitment source. In addition, the number of telephone calls generated by a particular recruitment method depends in part on the amount of money invested in the recruitment method. Therefore, a more relevant metric for investigators conducting clinical trials is the cost per randomized participant. Using this metric, the least expensive recruitment method was a community event ($4.17 per randomized participant) and the most expensive recruitment method was radio advertisement ($18,292 per randomized participant). In comparison, the cost per randomized participant was $4373 for television advertisements and $895 for direct mailings. Based on these results, community events appear to be the most cost-efficient method of PAD recruitment. However, it is not clear whether the community event cost calculations by Love et al. included costs required for study personnel time carrying out the ankle–brachial index (ABI) screening at the community event. This cost could be substantial, particularly if many people must be screened in order to identify one eligible PAD participant.

The data provided by Love et al. are informative for investigators conducting randomized clinical trials of participants with PAD. However, the following considerations should be made when interpreting their findings. First, Love et al. did not use medical centers as a recruitment source. Non-invasive vascular laboratories, vascular medicine and vascular surgery practices, cardiologists, and primary care physicians evaluate large volumes of patients with PAD each year and may represent valuable and cost-effective recruitment resources, particularly if the electronic health record can be used to generate lists of PAD patients who may be eligible. Since these lists can be generated efficiently and include people known to have PAD, this recruitment source may be more efficient than screening large numbers of people from the community, many of whom may be excluded because of a normal ABI value. Because Love et al. did not use medical centers for recruitment, the cost and yield of this recruitment source cannot be considered relative to the other recruitment sources reported. Second, an important metric for each recruitment method that was not emphasized by Love et al. consists of the number of screening telephone calls or study visits required to achieve one randomized participant. Although direct mailings and television advertisements yielded the greatest number of telephone calls, only 6% of telephone calls from direct mailings and only 4% of telephone calls from television advertisements resulted in randomized participants. In contrast, 28.6% of the telephone screenings from bus advertisements and 16.9% of all telephone screenings from community events resulted in randomized participants. Third, data on cost per randomized participant do not appear to include costs associated with staff time related to activities performed, such as obtaining informed consent and measuring the ABI for potential participants who were ineligible. Costs required for study staff members to attend community events and conduct large numbers of screenings may be substantial. Future cost analyses that more precisely take into account the total costs per randomized participant for each recruitment method may be valuable to study investigators. Fourth, it is likely that the most effective recruitment methods vary depending on the nature of the study intervention. For example, while direct mailings may be highly effective for a behavioral intervention of home-based exercise, they may be less useful for testing revascularization interventions in PAD.

Love et al. are to be commended on their success randomizing 174 participants with PAD over a 3.5-year period. This accomplishment is even more remarkable given that all enrolled participants were African American. Notably, Love et al. spent more than $343,000 on recruitment: a cost of approximately $100,000 per year. This cost should be considered in the context of the substantial benefit that may be experienced by millions of PAD patients if a new effective therapy for PAD-related functional impairment is identified. Recruitment costs are an important investment in the quest to identify new therapies to improve functional performance and prevent mobility loss in the large and growing numbers of people with PAD.

In recognition of the importance of more rapidly identifying new therapies for patients, the Patient-Centered Outcomes Research Institute (PCORI) funded the Patient-Centered Outcomes Research Network (PCORnet), a national network dedicated to accelerating research evidence generation by engaging multiple stakeholders and facilitating innovative research designs in order to accelerate evidence acquisition and improve patient care.^13,14 The overall goal of PCORnet is to conduct high quality clinical research more efficiently at lower costs. PCORnet includes multiple clinical data research networks that link health systems with electronic health records and access to more than 1 million patients per system. Although these clinical data research networks are designed to collect data quickly on large populations, including rare diseases, they are potentially useful tools to accelerate recruitment for randomized clinical trials. Future study should determine whether this method is effective in facilitating recruitment for trials of PAD participants.

Randomized trials of therapeutic interventions are urgently needed to identify effective and durable therapies for PAD-related walking impairment. Successful completion of these randomized trials requires achieving enrollment targets. The work by Love et al. and others^7,10 demonstrates that multiple recruitment sources are necessary, and that recruitment for PAD trials is costly. Resources and targeted interventions to increase enrollment are needed now to promote recruitment in clinical trials of PAD. Given the functional limitations and mobility loss experienced by patients with PAD, we cannot afford to wait.