A Systematic Search and Review of Registered Pharmacological Therapies Investigated to Improve Outcomes after a Stroke

Stroke is a major cause of death and disability with only a limited number of treatment options to improve functional outcomes or reduce death and disability after a stroke, including thrombolytic therapy, thrombectomy, early use of anti-platelets, decompression craniectomy for “malignant” infarcts, organized stroke care, and constraint-induced movement therapy [1]. However, many patients do not receive time-sensitive acute stroke therapies for various reasons [2, 3]. Alternative strategies using neuroprotectants have failed to live up to their earlier promise [4]. Drug interventions that mediate recovery beyond the acute windows are, therefore, clinically important research targets.

As much as three-quarters of all stroke patients suffer impairments and disabilities, the most common of which is motor weakness [5]. In a large multicenter clinical trial of stroke patients with a third of participants coming from Asia, at a median follow-up of 4 years, 19–22% were disabled and 12–14% were dependent, requiring regular help with everyday activities [6].

Stroke burden is largely due to long-term impairments suffered after a stroke, requiring long-term care and loss of productivity [7‒12]. Improving the degree and chances of recovery will translate to an overall reduction in the burden and cost of stroke care. Apart from standard rehabilitation strategies, however, there is currently no common recommendation on pharmacological treatment for stroke recovery. Clearly, treatments are needed to enhance recovery after stroke. Prematurely judging a treatment as ineffective may mean lost opportunities in moving stroke recovery research forward to benefit stroke sufferers. Conversely, claiming a treatment as effective, when there is a lack of evidence, can be problematic as patients may be exposed unnecessarily to possible side effects or miss the opportunity of receiving a more appropriate treatment, in addition to incurring the costs of an ineffective intervention. A review of registered pharmacological therapies that have been investigated for improving post-stroke outcomes will help identify the types of available evidence, information on how research was conducted on them, key characteristics or factors related to treatment effects and knowledge gaps in the pharmacological treatment of post-stroke patients that will be helpful in both clinical decision-making and planning future studies.

In this systematic search and review, we aim to identify and assess studies of different registered pharmacological therapies investigated for improving post-stroke impairments and/or disabilities. The research questions we seek to answer are as follows:

• 1.

  What is the best available evidence based on study design for different registered pharmacological therapies investigated for improving outcomes after a stroke?

• 2.

  What stroke sub-populations and post-stroke outcomes are improved by these treatments, if any?

This systematic search and review [13] was registered in the International Prospective Register of Systematic Reviews in 2022 (PROSPERO CRD42022376973).

Studies that have the following PICO study characteristics will be included in the review: participants (P), intervention (I), comparators (C), and outcomes (O).

Studies examining adult humans, aged 18 years or older, diagnosed with stroke will be included. Studies addressing both adults and children may be included if data provided for adults were reported separately.

Interventions are pharmacological therapies that have been investigated as recovery-enhancing or recovery-promoting treatments in patients who had suffered a stroke. These treatments must have received registration or market authorization in any country, either prescription or over-the-counter products, and may or may not have primary indications for use in other medical conditions. Table 1 lists the pharmacological classes and drugs to be included in the review.

Depending on study type, a comparator (active or placebo) may or may not be used. Any comparator will be accepted and reviewed.

Stroke-related outcomes include overall function and motor recovery. Other clinical neurological domains reported will also be considered. The following outcomes, however, will be excluded:

• Psychiatric – mood (e.g., depression, mania, anxiety, apathy), sleep disorder, hypersexuality, emotionalism, delirium, etc.

• Cognitive – dementia, memory impairment, concentration, neglect, etc.

• Spasticity, contracture, sialorrhea, seizures, pain, fatigue

• Imaging and laboratory outcomes (e.g., lesion size, vasospasm, biomarkers, transcranial magnetic stimulation parameters, etc.)

Literature search will be carried out in PubMed, EMBASE, Scopus, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects for published reports from the start of each respective database’s availability up to the actual date when the search is performed. Search will also be supplemented by searching for trial protocols at https://www.clinicaltrials.gov and completing systematic reviews in PROSPERO. The search criteria will include (1) both MeSH terms and free text related to “stroke” and “recovery”; (2) each of the pharmacological class/product listed, (3) limited to the English language and (4) human subjects only. Search strategy for EMBASE is shown in Table 2. The search syntax will be adjusted accordingly in each search engine with the same criteria. To ensure literature saturation, the reference lists of included studies or relevant reviews will be scanned.

Literature search results will be uploaded to Covidence (https://www.covidence.org), grouped by pharmacological class, to facilitate collaboration among reviewers during the study selection process. Duplicates will be identified and removed automatically by Covidence and by manual checking. Titles and abstracts screening will be conducted by at least one author and only relevant studies will be further retrieved and reviewed on full text of publication. Included studies will be classified into one of the categories in decreasing level of evidence: systematic review and/or meta-analysis, randomized controlled trial, nonrandomized controlled trial, cohort study, case-control study, case report, or opinion of expert(s).

Decision on selecting “the best available studies” based on study design will be made by 2 reviewers. If multiply papers are identified under the same hierarchy, decision will be reached by consensus based on study size and date of publication for different stroke subtypes and/or outcomes. Any disagreement on study selection and data extraction will be resolved by a third author.

Data extraction from studies included for full review will be performed using a pre-designed form for each included report. Data are extracted by a first reviewer and further confirmed by a second reviewer. In cases of ambiguity of information, the study will be elevated for adjudication.

Data extracted will include patient demographics (age, gender, country of origin), methodology (study design, sample size, keystroke inclusion criteria), intervention details (dosage, frequency, duration of intervention, type of control used), duration (stroke onset to study inclusion, follow-up period), and the reported outcomes (as dichotomous or continuous). If outcome is reported as a composite measure, individual outcomes as reported in the studies will be extracted, if available. Whenever possible, results from an intention-to-treat analysis will be used. For cross-over trials, data from the first period only will be extracted to avoid any possible carry-over effects, or the potential of stroke patients to recover spontaneously during cross-over.

Search results will be summarized in a PRISMA flow diagram. The selected studies will be grouped by pharmacological class/product and stroke subtypes with short narratives to highlight the important points. The level of evidence will be assessed according to the latest version of the American Stroke Association Level of Evidence scheme (Table 3) [14].

There are conflicting study results of pharmacological interventions after an acute stroke to enhance recovery [16]. For example, the FLAME trial showed the benefit at 3 months of fluoxetine combined with physiotherapy among patients with ischemic stroke and motor deficits [15]. Subsequent studies using functional assessment at 6 months follow-ups, however, were neutral [17‒19]. There is a large evidence base for amphetamines which has been shown in animal experiments to promote axonal sprouting into deafferented subcortical areas from contra-lesional projection neurons, as well as neurite growth followed by synaptogenesis in the neocortex [20‒22]. Clinical trials have shown no evidence at present to support the use of amphetamine after stroke, although there was a trend toward improved motor function [23]. Moreover, a 5-week trial of amphetamine in aphasia showed benefit at 6 months [24]. Another trial showed benefit in motor recovery at 1 and 12 months after drug discontinuation [25], suggesting that the beneficial effects of pharmacological interventions may occur or be maintained after the drug has been stopped. It is entirely possible that the apparent “lack” of efficacy of neurorestorative interventions thus far may not just be due to small sample sizes or varying severity of study subjects but also to premature summative assessment and that an assessment at an extended time frame might show positive effects.

Performing a systematic search and review will be ideal in addressing broad questions like ours that encompasses a wide range of treatments investigated for post-stroke recovery by incorporating different study types and providing a more complete picture of the research conducted [16]. The results of this review will be a “best evidence synthesis” in this field.

There are potential limitations in our study. Our critical review may be prone to the same limitations as a traditional review. We, therefore, included explicit inclusion and exclusion criteria and a clearly defined process of synthesis in our study design. No meta-analysis is planned as it may be performed on selected pharmacological classes or products based on this review in future systematic reviews. We will include only papers published in English and may exclude some well-conducted large studies published in other languages. We will also exclude studies that assessed psychiatric and cognitive outcomes, spasticity, seizures, pain and fatigue, as well as imaging and laboratory outcomes as surrogate markers. Nonetheless, our focus on treatments which are already available to clinicians and patients will help guide clinical decision-making.

As this is a review of reports from public databases and no individual human subject data are accessed, no ethical approval or participants’ consent are required.

T.-H.L., Y.K., H.C.C., K.S.T., J.D.P., L.G., and Y.W. have no relevant conflict of interest in this review to disclose. S.U. received funding for clinical trials related to edaravone but will not be involved in the assessment of edaravone for this review. J.C.N. received funding for clinical trials related to MLC601/MLC901, and N.V. received funding for clinical trials related to MLC601/MLC901 that were paid to his institution. They will not be involved in the assessment of MLC601/MLC901 for this review.

No funding was received for this review.

All authors contributed to the design of the study and have read and approved the content of this manuscript. T.-H.L. and N.V. approved the final protocol. L.G. and Y.W. will set up the Covidence platform, perform the searches, and manage the search results. T.-H.L., S.U., Y.K., H.C.C., J.C.N., K.S.T., J.D.P., ad N.V. will perform the screening and reviews of the study reports.

Data derived from this review will not be publicly available but will be available to researchers from the corresponding authors upon reasonable request.