Challenges in Screening and Recruitment for a Neuroimaging Study in Cognitively Impaired Geriatric Inpatients

Abstract

Background: Neuroimaging-based biomarkers have the potential to improve etiological diagnosis of cognitive impairment in elderly inpatients. However, there is a relative lack of studies on neuroimaging-based biomarkers in hospitalized geriatric patients, as the vast majority of neuroimaging studies in dementia have focused on memory clinic outpatients. An important aspect of study planning is a priori estimation of the rate of screen failures.

Objective: To report on the rate and causes of screen failures in a prospective study on the utility of neuroimaging (PET, MRI) for the etiological diagnosis of newly manifested cognitive impairment in acutely hospitalized geriatric patients.

Methods: Ten acute care geriatrics clinics with 802 beds participated in the study. The potential recruitment rate had been estimated to 5 patients/100 beds/week.

Results: Seventeen months of pre-screening resulted in 322 potential participants. 109 of these patients were enrolled, i.e., the screen failure rate was 66%. 58% of the screen failures were due to refusal of participation by the patient, most often due to lack of interest in clarifying the cause of the cognitive impairment or due to reluctance to engage in additional diagnostic procedures associated with physical stress. 42% of pre-screened patients were excluded because of violation of the eligibility criteria.

Conclusion: Enrollment for neuroimaging studies presents considerable additional challenges in acutely hospitalized geriatric patients compared to outpatient settings. Low rate of approaching potential candidates by attending geriatricians and a high rate of screen failures have to be anticipated in the study design.

Keywords

Clinical trial cognitive impairment geriatric inpatients neuroimaging recruitment failure

INTRODUCTION

Establishing the etiology of cognitive impairment is a very serious event for the patient and her or his relatives: individuals aged 60 or older are more afraid of Alzheimer’s disease (AD) than of cancer and stroke combined [1]. The etiological diagnosis of cognitive impairment, therefore, has to be as reliable and as accurate as possible.

In clinical routine, the etiological diagnosis of cognitive impairment relies on symptom-based criteria and brain imaging to exclude treatable causes such as subdural hematoma, brain tumor, or normal pressure hydrocephalus [2]. Diagnosis of AD based on symptoms alone, however, is prone to be inaccurate, particularly at earlier clinical stages and in cases with atypical clinical presentation [3]. Diagnostic accuracy can be improved by complementing the symptom-based criteria with biomarker-based evidence of the underlying pathophysiology [4 –7]. Biomarkers based on magnetic resonance imaging (MRI) or positron emission tomography (PET) of the brain are among the most promising biomarkers in this context. Yet, the vast majority of MRI and/or PET neuroimaging studies in AD have focused on outpatients with typical clinical presentations. There is a relative lack of AD biomarker studies in more difficult settings.

Patients hospitalized in a geriatric unit for an acute illness present such a difficult clinical setting. A particular diagnostic dilemma is presented by patients with first clinical manifestation of a potential neurodegenerative disease during their current hospital stay. On the one hand, cognitive impairment occurring within days to weeks during hospitalization excludes making the diagnosis of probable AD according to current guidelines, since these require gradual onset of cognitive decline over months to years [4 , 7]. On the other hand, these patients, too, might benefit from a clear diagnosis and treatment recommendations before they are discharged from the geriatrics unit [8]. Neuroimaging might resolve this dilemma by establishing or excluding AD pathophysiological processes. Testing this hypothesis relies upon clinical trials for the validation of neuroimaging for this specific indication, which, however, face numerous challenges [9 –13]. Recruitment and retention of older adults in clinical trials is impeded by various factors including multiple comorbid conditions, decreased life expectancy, socioeconomic factors, ethical challenges, lack of compliance, and refusal to participate in clinical trials due to frailty and vulnerability [11 –14]. Hospitalization in an acute care geriatrics unit presents additional obstacles such as the requirement of intensive cooperation from the geriatrics unit despite busy daily routine [13]. Thus, reliable recruitment planning is particularly complex in the geriatric inpatient setting.

An important aspect of recruitment planning is a priori estimation of the rate of screen failures. Here we report on the rate and causes of screen failures in a prospective multicenter neuroimaging study in acutely hospitalized geriatric patients with newly manifested cognitive impairment. Understanding the causes of screen failures might help to improve recruitment strategies for reduced screen failure rate of future studies in this increasingly relevant clinical setting. This is important, as low participation rates not only lead to delay and increased costs but also might cause sampling bias that might invalidate the results [15].

MATERIALS AND METHODS

Study

All data were derived from the prospective clinical trial “Comparison and integration of modalities in the early and differential diagnosis of dementing disorders in hospitalized geriatric patients: a prediction study” (WHO Trials Registry DRKS00005041). This investigator-initiated trial was approved by the German Federal Institute for Drugs and Medical Devices as phase III trial of brain PET with the glucose analog F-18-fluorodeoxyglucose (FDG) for the diagnosis of cognitive impairment (reference 61-3910-4039304; EudraCT 2013-000140-2). Ethics approval was obtained from the ethics committee of the state of Berlin (13/0234-EK12).

Primary inclusion criterion was cognitive impairment that had manifested during the hospital stay and remained unclear after standard clinical assessment (the full list of eligibility criteria is given in the Supplementary Material).

Study procedures included standardized patient history, physical/neurological examination, blood/urine laboratory tests, detailed neuropsychological testing, MRI of the brain, FDG PET of the brain, and ApoE genotyping. Lumbar puncture for analysis of cerebrospinal fluid was optional.

Ten acute care geriatrics clinics in Berlin with in total 802 beds participated in the recruitment.

Initialization visit

There was a standardized on-site study initiation at each participating geriatrics clinic. The initiation covered information about the aims of the study, the screening algorithm (Fig. 1a), study procedures, visit plan (Fig. 1b), criteria for assessment of the patient’s competence for consenting in participation in the study [16], and contact information (mobile phone for immediate contact with a study physician). A two-page leaflet summarizing this information was given to all geriatricians and neuropsychologists of the geriatrics clinic.

The geriatrics clinics were motivated to recruit patients for the study by offering short-term feedback on the result of each study-related examination, i.e., an extensive diagnostic workup for clarification of the clinically uncertain cognitive impairment of their patients without cost.

Screening and inclusion of patients

Screening comprised two steps. Initial assessment (pre-screening) was conducted by the attending geriatrician (or neuropsychologist) in the geriatrics clinic. The attending geriatrician approached patients who seemed eligible for the study (legally competent and without obvious violation of eligibility criteria) and informed them about the study. The patients were given a four-page leaflet (Supplementary Material). The attending geriatrician asked the patients if they would be inclined to participate. If a patient considered participation, the attending geriatrician made an appointment for the study physician to visit the patient (second screening step).

The study physician visited the patient in the geriatrics clinic. If possible, a family member was engaged. The study physician provided detailed information about the study. Besides information about possible adverse events, he or she pointed out that the study involved two imaging sessions, MRI and PET of the brain, both at an external hospital with between 10 and 45 min one-way travel time by patient transport ambulance. The patient was also informed about the possible benefits of participation in the study such as intensive diagnostics beyond standard clinical workup, which might clarify the cause underlying her/his current cognitive impairment, which in turn might result in more specific treatment. The patient was also assured that non-participation would not cause any disadvantages or change in her/his current management. The patient was informed that she or he could withdraw at any time from all or part of the study. Finally, the patient was offered an expense allowance of 50 € for participation in the study. If the patient still considered participation after detailed information, she or he was given at least 24 h for further reflection, i.e., a second appointment with the study physician at least 24 h later was made. If the patient consented for participation in the study after this reflection period, the study physician completed detailed testing of the eligibility criteria. The study physician enrolled the patient if all eligibility criteria were met.

Screen failures

Patients who successfully passed pre-screening but were not enrolled were considered screen failures. Screen failures were divided into (a) patients who refused participation (at the first or at the second visit of a study physician) and (b) patients who were excluded due to violation of eligibility criteria. For patients who refused participation, the study physician categorized the primary reason for which they refused according to the following categories: (i) patient denies cognitive impairment, (ii) patient is not interested in clarifying the cause of her/his cognitive impairment, because she or he wants her/his acute medical problem (that led to the hospitalization) to be taken care of first, or because of indifference (e.g., associated with depression), or because of general rejection of participation in any kind of medical research, (iii) patient is reluctant to engage in the additional effort because of the physical stress associated with it, (iv) patient expressed fear of neuroimaging (confined space in the MRI and PET scanner), (v) patient is in fear of the diagnosis of AD, (vi) participation was rejected by a relative of the patient, (vii) patient was discharged from the hospital against physician’s advice.

RESULTS

During the recruitment phase of 17 months in the 10 participating geriatrics clinics with in total 802 beds, 322 patients passed pre-screening by the attending geriatrician and were screened by a study physician. Thus, the number of screened patients was considerably smaller than the expected number of 2,950 possible candidates (based on the estimated recruitment rate of 5 patients/100 beds/week).

109 of the 322 screened patients were enrolled (34%), resulting in a screen failure rate of 66%. The screening flowchart is shown in Fig. 2.

124 of the 213 screen failures were due to refusal of participation by the patient (58% of the screen failures, 39% of all screened patients). The frequency distribution of primary reasons for refusal is given in Fig. 3a.

89 of the screen failures were due to violation of eligibility criteria (42% of the screen failures, 28% of all screened patients). The frequency of specific eligibility criteria violated by pre-screened patients is given in Fig. 3b.

Six enrolled patients withdraw their consent prior to the first study-related procedure, reducing the number of patients with study data to 103. Brain MRI was completed by 90 of these patients (it was rejected by 2 patients, aborted during the 45 minutes scan by 11 patients). FDG PET was completed by 97 patients (rejected by 4 patients, aborted during the 20 minutes scan by 2 patients). Both MRI and FDG PET were completed in 88 patients. Only 12 of the 103 patients with study data had consented to lumbar puncture.

DISCUSSION

The screen failure rate was as large as two-thirds, although patients were pre-screened by their attending geriatrician. Over half of the screen failures (58%) were due to refusal of participation by the patient; the remaining screen failures (42%) were due to violation of the eligibility criteria.

Refusal of participation by the patient

The most relevant causes for refusal of participation by the patient were lack of interest in clarifying the cause of the cognitive impairment and reluctance to engage in additional diagnostic procedures associated with physical stress. The lack of interest was due to the acute somatic medical problem (which had led to the hospitalization of the patient) in about 50% of the “not interested” cases. These patients wanted her/his acute medical problem to be taken care of first. This is in agreement with reports that hospitalized patients with a more acute severe medical condition are principally less receptive to study participation [13, 17]. Refusal because of indifference (e.g., associated with depression) occurred with about the same frequency, whereas general rejection of participation in any kind of medical research was the reason for participant refusal in only a few single cases. Insufficient understanding of the benefits of participating in the study might also have contributed to the lack of interest [18], although substantial efforts were made to inform the patients about potential benefits of the more detailed diagnostic workup provided by the study. The acute medical problem and the patients’ reduced general health also contributed to the high rate of reluctance to engage in the additional effort (physical stress), not only of the patients themselves but also of their relatives, as additional physical stress to the patient was the most frequent cause for rejection by patients’ relatives.

The need for transportation to external sites for neuroimaging was a particularly large obstacle for many patients (and/or their relatives). In order to characterize a possible impact of travel time on the rate of refusal of participation, travel time to the MRI facility (MRI was planned to be performed prior to PET) was compared between all patients who refused participation for a reason that might have included travel time as a major component against all other screened patients (including patients who rejected participation for another reason, patients who were excluded because of violation of eligibility criteria and all enrolled patients). Travel time from the geriatrics clinics to MRI was estimated by Google maps. The following reasons for refusal of participation were considered to possibly include travel time as a major component (comp. Fig. 3): “additional effort”, “not interested”, “participation rejected by a relative”, and “fear of medical imaging”. Estimated travel time to MRI was not different between patients who refused participation because of one of these reasons (n = 103) and the other screened patients (n = 219): one-way travel time was 26.6±4.1 min versus 27.1±5.6 min (t-test p = 0.412). Nevertheless, the need to travel to the imaging procedures probably was a relevant deterrent for participation in the study. It therefore might be recommended to restrict recruitment of geriatric inpatients for neuroimaging studies to hospitals with the corresponding imaging facilities on-site. Improved logistics and patient comfort might be achieved by employing hybrid modality PET-MRI systems which allow simultaneous acquisition of MRI and PET within a single imaging session [19].

Fear of the diagnosis of AD was the third most frequent cause for refusal of participation. This is in line with the fact that AD and dementia are the medical conditions elderly people are most afraid of getting [1]. Fear of the diagnosis involves fear of stigmatization, of paternalism, of incapacitation, and of the inability to care for oneself and to sustain the accustomed lifestyle [20 –23]. Furthermore, patients are aware that there are currently no therapies to cure AD. When trying to address fear of AD, it is important to respect the patient’s right not to know the etiology of her/his cognitive impairment [15].

Previous studies have identified many variables that impact on the recruitment and retention of clinical trial subjects. Curiosity is an important pre-enrollment motivator, whereas personal benefit, interest in research, and altruism are more relevant in the enrollment phase. Regular health monitoring is an additional recompense for older recruits [24]. However, these motivators, effective for healthier and less frail outpatient subjects, are probably less effective in geriatric patients hospitalized for an acute medical problem.

Violation of eligibility criteria

By far the most frequent cause for exclusion of a patient was violation of the MRI-specific criteria by pacemakers or other implants, which are relatively frequent in elderly inpatients. The second most frequent cause for exclusion was that the general health condition of the patient did not allow participation in the trial, either because of unstable serious somatic condition or because of proof of resistant nosocomial pathogens which is quite often met in geriatric inpatients with prolonged stay, but rarely inoutpatients.

Barriers for pre-screening

The potential recruitment rate had been estimated to 5 patients/100 beds/week, based on prospective evaluation of all patients for eligibility in one of the participating geriatrics clinics for several months. Thus, 17 months recruitment in 10 participating geriatrics clinics with in total 802 beds was expected to result in about 2,950 possible candidates for participation in the study. The fact that only about 10% of this number of candidates were seen by a study physician in the second screening phase strongly suggests that only a fraction of the possible candidates were approached by the attending geriatrician. Thus, pre-screening was a large obstacle in this study, although the missing rate was probably smaller than 90%, as screen failure during pre-screening by the attending geriatrician was not documented. The rate of pre-screening might have been improved by asking each of the participating geriatrics clinics to maintain a local list of newly admitted patients in which the attending geriatrician (or neuropsychologist) documents whether or not the new patient is a potential candidate for the study, and if not, why not.

Pre-screening items included assessment of the patient’s competence for consenting in participation in the study. It is possible that this precluded patients being approached, as the decision whether or not a patient has the competence to consent in participation in a study imposes considerable additional responsibility.

The acute somatic disease that led to the admission in the geriatrics clinic requires the primary attention of the attending geriatrician. Screening patients for participation in a clinical study has clearly lower priority [11]. Screening is further complicated by efforts to shorten the duration of the hospital stay as much as possible, so that there is only a short time interval to screen, approach, and enroll a patient [13, 25]. In order to address this challenge, the tasks of the attending geriatrician were restricted to pre-screening based on a short and concise algorithm (Fig. 1a). Once a patient had passed pre-screening, study personnel took over. In addition, the result of each diagnostic procedure was provided promptly so that the attending geriatrician could integrate it in the diagnostic workup.

Finally, dementia is still a taboo subject and there is a tendency to avoid bringing bad news, such as disclosing a diagnosis of AD [26]. Neuropsychologists in geriatrics clinics can help to address this taboo and to facilitate communication with the patient [27]. However, probably more important are ethical considerations of the geriatricians (“What’s the benefit of an additional AD diagnosis for very old and multimorbid patients with limited life expectancy?”). In addition, caregivers face emotional burdens to increase the patient’s physical and emotional stress by participating in a clinical study. These aspects should be taken into account when defining the target population of a study.

Limitations

The exclusion of patients with suspicion of neurodegenerative disease other than AD such as frontotemporal lobar degeneration and Morbus Parkinson with dementia/Lewy body disease (E4 in the Supplementary Material) should be mentioned as a limitation of the present study, since non-AD neurodegenerative diseases are also diagnostically relevant in the geriatric inpatient setting. Searching the database of patients in one of the participating geriatrics clinics during the planning phase of the study showed the number of patients diagnosed with a non-AD neurodegenerative disease to be very small, less than 10% of the number of AD diagnoses. Although this probably underestimates the frequency of non-AD neurodegenerative diseases in the geriatric inpatient setting, it was the rationale for excluding non-AD neurodegenerative diseases in this study.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the Regional Development Fund of the European Union (10153407, 10153971, 10153458, 10153460, 10153461, 10153462, 10153463).

Authors’ disclosures available online ().

Appendix

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