Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions

Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke

Swallowing therapy for dysphagia in acute and subacute stroke

Background: Dysphagia (swallowing problems), which is common after stroke, is associated with increased risk of death or dependency, occurrence of pneumonia, poor quality of life, and longer hospital stay. Treatments provided to improve dysphagia are aimed at accelerating recovery of swallowing function and reducing these risks. This is an update of the review first published in 1999 and updated in 2012.Objectives: To assess the effects of swallowing therapy on death or dependency among stroke survivors with dysphagia within six months of stroke onset.Search methods: We searched the Cochrane Stroke Group Trials Register (26 June 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library (searched 26 June 2018), MEDLINE (26 June 2018), Embase (26 June 2018), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (26 June 2018),Web of Science Core Collection (26 June 2018), Speech BITE (28 June 2016), ClinicalTrials.Gov (26 June 2018), and the World Health Organization International Clinical Trials Registry Platform (26 June 2018). We also searched Google Scholar (7 June 2018) and the reference lists of relevant trials and review articles.Selection criteria: We sought to include randomised controlled trials (RCTs) of interventions for people with dysphagia and recent stroke (within six months).Data collection and analysis: Two review authors independently applied the inclusion criteria, extracted data, assessed risk of bias, used the GRADE approach to assess the quality of evidence, and resolved disagreements through discussion with the third review author (PB). We used random effects models to calculate odds ratios (ORs), mean differences (MDs), and standardised mean differences (SMDs), and provided 95% confidence intervals (CIs) for each. The primary outcome was functional outcome, defined as death or dependency (or death or disability), at the end of the trial. Secondary outcomes were case fatality at the end of the trial, length of inpatient stay, proportion of participants with dysphagia at the end of the trial, swallowing ability, penetration aspiration score, or pneumonia, pharyngeal transit time, institutionalisation, and nutrition.Main results: We added 27 new studies (1777 participants) to this update to include a total of 41 trials (2660 participants). We assessed the efficacy of swallowing therapy overall and in subgroups by type of intervention: acupuncture (11 studies), behavioural interventions (nine studies), drug therapy (three studies), neuromuscular electrical stimulation (NMES; six studies), pharyngeal electrical stimulation (PES; four studies), physical stimulation (three studies), transcranial direct current stimulation (tDCS; two studies), and transcranial magnetic stimulation (TMS; nine studies). Swallowing therapy had no effect on the primary outcome (death or dependency/disability at the end of the trial) based on data from one trial (two data sets) (OR 1.05, 95% CI 0.63 to 1.75; 306 participants; 2 studies; I² = 0%; P = 0.86; moderate-quality evidence). Swallowing therapy had no effect on case fatality at the end of the trial (OR 1.00, 95% CI 0.66 to 1.52; 766 participants; 14 studies; I² = 6%; P = 0.99; moderate-quality evidence). Swallowing therapy probably reduced length of inpatient stay (MD -2.9, 95% CI -5.65 to -0.15; 577 participants; 8 studies; I² = 11%; P = 0.04; moderate-quality evidence). Researchers found no evidence of a subgroup effect based on testing for subgroup differences (P = 0.54). Swallowing therapy may have reduced the proportion of participants with dysphagia at the end of the trial (OR 0.42, 95% CI 0.32 to 0.55; 1487 participants; 23 studies; I² = 0%; P = 0.00001; low-quality evidence). Trial results show no evidence of a subgroup effect based on testing for subgroup differences (P = 0.91). Swallowing therapy may improve swallowing ability (SMD -0.66, 95% CI -1.01 to -0.32; 1173 participants; 26 studies; I² = 86%; P = 0.0002; very low quality evidence).We found no evidence of a subgroup effect based on testing for subgroup differences (P = 0.09). We noted moderate to substantial heterogeneity between trials for these interventions. Swallowing therapy did not reduce the penetration aspiration score (i.e. it did not reduce radiological aspiration) (SMD -0.37, 95% CI -0.74 to -0.00; 303 participants; 11 studies; I² = 46%; P = 0.05; low-quality evidence). Swallowing therapy may reduce the incidence of chest infection or pneumonia (OR 0.36, 95% CI 0.16 to 0.78; 618 participants; 9 studies; I² = 59%; P = 0.009; very low-quality evidence).Authors’ conclusions: Moderate- and low-quality evidence suggests that swallowing therapy did not have a significant effect on the outcomes of death or dependency/disability, case fatality at the end of the trial, or penetration aspiration score. However, swallowing therapy may have reduced length of hospital stay, dysphagia, and chest infections, and may have improved swallowing ability. However, these results are based on evidence of variable quality, involving a variety of interventions. Further high-quality trials are needed to test whether specific interventions are effective

Should we adjudicate outcomes in stroke trials? A systematic review

BACKGROUND: Central adjudication of outcomes is common in randomized clinical trials in stroke. The rationale for adjudication is clear; centrally adjudicated outcomes should have less random and systematic errors than outcomes assessed locally by site investigators. However, adjudication brings added complexities to a clinical trial and can be costly. AIM: To assess the evidence for outcome adjudication in stroke trials. SUMMARY OF REVIEW: We identified 12 studies evaluating central adjudication in stroke trials. The majority of these were secondary analyses of trials, and the results of all of these would have remained unchanged had central adjudication not taken place, even for trials without sufficient blinding. The largest differences between site-assessed and adjudicator-assessed outcomes were between the most subjective outcomes, such as causality of serious adverse events. We found that the cost of adjudication could be upward of £100,000 for medium to large prevention trials. These findings suggest that the cost of central adjudication may outweigh the advantages it brings in many cases. However, through simulation, we found that only a small amount of bias is required in site investigators’ outcome assessments before adjudication becomes important. CONCLUSION: Central adjudication may not be necessary in stroke trials with blinded outcome assessment. However, for open-label studies, central adjudication may be more important

The pattern of penetration and aspiration in acute stroke survivors

Background and Aims: Aspiration is common in acute stroke survivors with dysphagia, is associated with increased pneumonia rates, and is an independent predictor of mortality. However, studies evaluating the nature and pattern of penetration and aspiration post-stroke are lacking. Method: The Penetration-Aspiration Scale (PAS) was used to rate baseline videofluoroscopic swallowing studies of 17 dysphagic stroke survivors from the STEPS trial of pharyngeal electrical stimulation (onset <14 days, mean 74 years). Analysis was performed on 6 x 5ml boli and 1 x 50ml bolus (thin fluids with contrast agent at 40% wt/vol), recorded at 25 f/s. Every swallow to clear each 5ml or 50ml bolus was counted, given a PAS score and labelled a primary or secondary (clearing) swallow. Results: In total, 285 swallows were viewed. Due to poor image quality, 7% of swallows were excluded. At a bolus level, for 5ml/50ml swallows, results showed 68%/42% normal swallows, 14%/27% penetration and 18%/31% aspiration respectively. At a subject level, 5ml: only 3 patients scored within normal limits for all boli; 50ml: no subject swallowed without showing penetration or aspiration at some point. Higher penetration and aspiration scores occurred on 50ml. Aspirated material was rarely fully cleared, even in those subjects who demonstrated a cough response (5ml: 2%, 50 ml: 0%). Conclusion: Aspiration in post-stroke dysphagia appears to fluctuate in presentation within and between boli. Bedside assessments should take into account variability and sample enough swallows. In addition, clinicians should not assume coughing clears aspirated material. Quality of image capture must be optimised for future studies

Acute treatment of stroke (except thrombectomy)

Purpose of Review: The management of patients with acute stroke has been revolutionized in recent years with the advent of new effective treatments. In this rapidly evolving field, we provide an update on the management of acute stroke excluding thrombectomy, looking to recent, ongoing, and future trials.Recent Findings: Large definitive trials have provided insight into acute stroke care including broadening the therapeutic window for thrombolysis, alternatives to standard dose alteplase, the use of dual antiplatelet therapy early after minor ischemic stroke, and treating elevated blood pressure in intracerebral hemorrhage. Further ongoing and future trials are eagerly awaited in this ever-expanding area.Summary: Although definitive trials have led to improvements in acute stroke care, there remains a need for further research to improve our understanding of pathophysiological mechanisms underlying different stroke types with the potential for treatments to be tailored to the individual

Elevated plasminogen activators are associated with hematoma progression in spontaneous intracerebral hemorrhage

Endogenous fibrinolysis might lead to hematoma progression in spontaneous intracerebral hemorrhage (ICH). We studied plasma biomarkers of fibrinolysis and hemostasis in twenty-two patients with ICH and nine healthy controls (HC) in a single-center study. Patients with ICH had significantly higher D-dimer and plasmin-alpha-2-antiplasmin complexes compared to HC. At baseline, patients with hematoma progression had higher urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) and lower plasminogen levels, compared to those with no progression. 24-hour and day-7 matrix metalloproteinase-9 (MMP-9) was significantly increased in patients with hematoma progression

Analysis of the Modified Rankin Scale in Randomised Controlled Trials of Acute Ischaemic Stroke: A Systematic Review

Background. Historically, most acute stroke clinical trials were neutral statistically, with trials typically dichotomising ordinal scales, such as the modified Rankin Scale. Studies published before 2007 have shown that preserving the ordinal nature of these scales increased statistical power. A systematic review of trials published since 2007 was conducted to reevaluate statistical methods used and to assess whether practice has changed. Methods. A search of electronic databases identified RCTs published between January 2007 and July 2014 in acute ischaemic stroke using an ordinal dependency scale as the primary outcome. Findings. Forty-two RCTs were identified. The majority used a dichotomous analysis (25, 59.5%), eight (21.4%) retained the ordinal scale, and nine (19.0%) used another type of analysis. Conclusions. Trials published since 2007 still favoured dichotomous analyses over ordinal. Stroke trials, where appropriate, should consider retaining the ordinal nature of dependency scales

Short email with attachment versus long email without attachment when contacting authors to request unpublished data for a systematic review: a nested randomised trial

Objective: Systematic reviews often rely on the acquisition of unpublished analyses or data. We carried out a nested randomised trial comparing two different approaches for contacting authors to request additional data for a systematic review. Participants: Participants were authors of published reports of prevention or treatment trials in stroke in which there was central adjudication of events. A primary and secondary research active author were selected as contacts for each trial. Interventions: Authors were randomised to be sent either a short email with a protocol of the systematic review attached (“Short”), or a longer email that contained detailed information and without the protocol attached (“Long”). A maximum of two emails were sent to each author to obtain a response. The unit of analysis was trial, accounting for clustering by author.Primary and secondary outcome measures: The primary outcome was whether a response was received from authors. Secondary outcomes included time to response, number of reminders needed before a response was received and whether authors agreed to collaborate.Results: 88 trials with 76 primary authors were identified in the systematic review, and of these, 36 authors were randomised to Short [trials=45], and 40 to Long [trials=43]. Responses were received for 69 trials. There was no evidence of a difference in response rate between trial arms (Short vs Long, odds ratio 1.10, 95% C.I: [0.36, 3.33]). There was no evidence of a difference in time to response between trial arms (Short vs Long, hazard ratio 0.91, 95% C.I: [0.55, 1.51]). In total, 27% of authors responded within a day and 22% of authors never responded. Conclusions: There was no evidence to suggest that email format had an impact on the number of responses received when acquiring data for a systematic review involving stroke trials, or the time taken to receive these responses

The effect of different combinations of vascular, dependency and cognitive endpoints on the sample size required to detect a treatment effect in trials of treatments to improve outcome after lacunar and non-lacunar ischaemic stroke

Background Endpoints that are commonly used in trials of moderate/severe stroke may be less frequent in patients with minor, non-disabling stroke thus inflating sample sizes. We tested whether trial efficiency might be improved with composite endpoints. Methods We prospectively recruited patients with lacunar and minor non-lacunar ischaemic stroke (NIHSS ≤ 7) and assessed recurrent vascular events (stroke, transient ischaemic attack (TIA), ischemic heart disease (IHD)), modified Rankin Score (mRS) and cognitive testing with the Addenbrooke’s Cognitive Examination (ACE-R) one year post-stroke. For a potential secondary prevention randomised controlled trial (RCT), we estimated sample sizes using individual or combined outcomes, at power 80% (and 90%), alpha 5%, required to detect a relative 10% risk reduction. Results Amongst 264 patients (118 lacunar, 146 non-lacunar), at one year, 30/264 (11%) patients had a recurrent vascular event, 5 (2%) had died, 3 (1%) had clinically-diagnosed dementia, 53/264 (20%) had mRS ≥ 3 and 29/158 (19%) had ACE-R ≤ 82 (57 could not attend for cognitive testing). For a potential trial, at 80% power, using mRS ≥ 3 alone would require n > 5000 participants, recurrent vascular events alone n = 9908 participants, and a composite of any recurrent vascular event, ACE-R ≤ 82, dementia or mRS ≥ 2 (present in 56% of patients) n = 2224 patients. However, including cognition increased missing data. Results were similar for lacunar and non-lacunar minor ischaemic stroke. Conclusions Composite outcomes including vascular events, dependency, and cognition reduce sample size and increase efficiency, feasibility, and relevance to patients of RCTs in minor ischaemic stroke. Efficiency might be improved further with more practical cognitive test strategies