Translational neurorehabilitation research in the third world: what barriers to trial participation can teach us

Abstract

Background and Purpose

Most stroke rehabilitation studies have been performed in high-income countries. The aim of this study was to identify the main barriers for patient inclusion in a research protocol performed in Brazil.

Methods

We evaluated reasons for exclusion of patients in a pilot, randomized, double-blinded clinical trial of stroke rehabilitation. Descriptive statistical analysis was performed.

Results

Only 5.6% of 571 screened patients were included. Recurrent stroke was responsible for exclusion of 45.4% of potentially eligible patients.

Conclusions

Recurrent stroke represented a big barrier to enroll patients in the protocol. External validity of rehabilitation trials will benefit from definition of study criteria according to regional characteristics of patients, including rates of recurrent stroke.

Clinical Trial Registration-URL: http://www.clinicaltrials.gov (NCT01333579)

Introduction

Two thirds of strokes occur in low- and middle-income countries, where stroke incidence has increased 100% in the past four decades¹. Disability in survivors presents escalating challenges to health care. Novel, cost-effective rehabilitation strategies are deeply needed.

Rehabilitation research has steadily grown in the past decade. Still, the vast majority of rehabilitation trials for patients with stroke have been performed in high-income Western countries². Difficulties in patient recruitment represent a big barrier to advances in the field, even in high-income areas^3,4. Reasons for the paucity of trials in low- and middle-income countries likely include lack of funding and skilled personnel for research, but local conditions and characteristics of patients with stroke in these areas are equally important³. Strategies not only must be cost effective but also deliverable in the societal context. In order to build evidence-based rehabilitation treatments adapted to real-world conditions, it is crucial to understand differences in obstacles for inclusion of patients in stroke rehabilitation protocols across low-, middle- and high-income countries.

Among the many gaps in knowledge that must be addressed by stroke rehabilitation research, improvement of upper limb function deserves special attention because 30–66% of hemiplegic patients do not gain arm function 6 months after stroke⁵ and evidence-based rehabilitation strategies to improve arm and hand function are scarce². Because of the issues outlined above, in depth data on patient profiles and recruitment characteristics were acquired for a proof-of-principle clinical trial on upper limb motor rehabilitation conducted in Brazil, to obtain a better picture on the sources of barriers to participation in rehabilitation trials.

Methods

Study Design

We prospectively evaluated reasons for exclusion of patients in a pilot, randomized, double-blinded clinical trial performed at Hospital das Clinicas/Sao Paulo University, the largest hospital in South America with 2200 beds⁶. Sao Paulo is the biggest Brazilian city, with an estimated population of 20 million in its metropolitan area. In this trial, patients with first-ever ischemic stroke were randomized for treatment with physical therapy and either low-frequency repetitive transcranial magnetic stimulation (rTMS) of the contralesional hemisphere, or sham rTMS. Results have been published elsewhere⁷.

Patients admitted to the Neurology Emergency Room were screened from February, 2008 to December, 2011 by evaluation of medical files and interviews about their clinical conditions. Inclusion and exclusion criteria are described in Figure 1. If inclusion and exclusion criteria were fulfilled, patients were contacted by phone after discharge, to schedule an evaluation to recheck eligibility.

Figure 1.

Flowchart

Exclusion criteria were evaluated sequentially according to the numeric order listed in Figure 1. For instance, if a patient had history of previous stroke, other criteria were not checked. Descriptive statistical analysis was performed. Continuous data are shown as means and standard deviations. Categorical data are shown as frequencies.

Results

The trial’s flowchart is shown in Figure 1. The average age (± standard deviation) of patients screened for the protocol was 61.6±15.0 years. 57% (n=325) of the patients were male. 20% (n=114) were Afro-Brazilian, 78% (N=444) were White and 2% (N=13) were Asian.

Complete information for screening was retrieved from 571 patients. Only 5.6% (32) of them were included.

Table 1 shows the counts/percentages of patients who did not fulfill inclusion criteria and Table 2, of patients who fulfilled inclusion criteria but presented exclusion criteria. A total of 124/273 (45.5%) patients who fulfilled inclusion criteria were excluded due to history of previous stroke.

Table 1.

Inclusion criteria. Numbers (percentages in parenthesis) of patients who did not fulfill these criteria.

Inclusion criteria	Did not fulfill inclusion criteria (n, %)
18 – 80 years	59 (22.2)
Ischemic stroke (up to 50% of the internal carotid artery territory)	142 (53.4)
Mild to severe hand paresis	61 (22.9)
5–45 days after stroke	4 (1.5)
Total	266 (100)

Table 2.

Numbers (percentages) of patients who fulfilled inclusion criteria, but presented exclusion criteria

Exclusion criteria	Fulfilled inclusion criteria but had exclusion criteria (n, %)
Recurrent strokes	124 (45.4)
Uncontrolled medical conditions	47 (17.2)
Contraindications to TMS	32 (11.7)
Not reached by phone after discharge	19 (7.0)
Could not comply with the protocol schedule	18 (6.6)
Inability to provide informed consent due to severe language or cognitive impairment	14 (5.1)
Did not agree to participate	9 (3.3)
Other neurologic or chronic diseases	7 (2.6)
Psychiatric or behavioral problems	3 (1.1)
Total	273 (100)

TMS=transcranial magnetic stimulation

Discussion

Almost half of the patients who fulfilled the inclusion criteria were excluded due to history of previous stroke. In Brazil, more than one-third of all strokes were recurrent in a population-based study (42.6%)⁸ and in a hospital-based study (42.9%)⁹. These rates are higher than those reported in high-income countries (20–30%)¹⁰, in line with reports of greater stroke recurrence in populations that have lower socioeconomic status¹¹. Therefore, it is expected that recurrent strokes represent a big barrier to rehabilitation research in low- and middle-income countries if recurrent stroke is an exclusion criterion.

In contrast, in Extremity Constraint Induced Therapy Evaluation (EXCITE), a multicenter study performed in a high-income country (United States), recurrent stroke accounted for 9% of exclusions^12,13. Inclusion and exclusion criteria were not exactly the same, but were comparable between EXCITE and the present study. To the best of our knowledge, EXCITE is the only clinical trial on upper paresis rehabilitation reporting exclusion statistics that allows for comparison with our own data.

Clinical research is always faced with the conundrum of the need for methodological rigor versus the need for applicability of the intervention to the wider population. Whereas explanatory studies are designed to identify mechanisms, pragmatic trials are conducted to provide a systematic assessment of feasible interventions¹⁴. In many third world environments, the need for clinically relevant research requires an adaptation of protocols to local needs and population characteristics.

Conclusion

Despite studies indicating that functional prognosis in patients with recurrent strokes is not necessarily worse than after first-ever stroke¹⁰, rehabilitation trials often exclude patients with recurrent strokes. Considering that 85% of all strokes occur in low- and middle-income countries where rates of recurrence are relatively high¹⁵, rehabilitation protocols with less exclusive criteria are deeply needed to have appropriate external validities. This approach, expected to foster development of interventions under realistic conditions, is faced with a number of difficulties including development of research infrastructure and funding. No matter how daring, the global burden of stroke is worthwhile the effort.