Sandeep Ankolekar

Feasibility of an Ambulance-Based Stroke Trial, and Safety of Glyceryl Trinitrate in Ultra-Acute Stroke The Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824)

Background and Purpose— The practicalities of doing ambulance-based trials where paramedics perform all aspects of a clinical trial involving patients with ultra-acute stroke have not been assessed. Methods— We performed a randomized controlled trial with screening, consent, randomization, and treatment performed by paramedics prior to hospitalization. Patients with probable ultra-acute stroke (<4 hours) and systolic blood pressure (SBP) >140 mm Hg were randomized to transdermal glyceryl trinitrate (GTN; 5 mg/24 hours) or none (blinding under gauze dressing) for 7 days with the first dose given by paramedics. The primary outcome was SBP at 2 hours. Results— Of a planned 80 patients, 41 (25 GTN, 16 no GTN) were enrolled >22 months with median age [interquartile range] 79 [16] years; men 22 (54%); SBP 168 [46]; final diagnosis: stroke 33 (80%) and transient ischemic attack 3 (7%). Time to randomization was 55 [75] minutes. After treatment with GTN versus no GTN, SBP at 2 hours was 153 [31] versus 174 [27] mm Hg, respectively, with difference −18 [30] mm Hg (P=0.030). GTN improved functional outcome with a shift in the modified Rankin Scale by 1 [3] point (P=0.040). The rates of death, 4 (16%) versus 6 (38%; P=0.15), and serious adverse events, 14 (56%) versus 10 (63%; P=0.75), did not differ between GTN and no GTN. Conclusions— Paramedics can successfully enroll patients with ultra-acute stroke into an ambulance-based trial. GTN reduces SBP at 2 hours and seems to be safe in ultra-acute stroke. A larger trial is needed to assess whether GTN improves functional outcome. Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN66434824/66434824. Unique identifier: 66434824.

Clinical trials for preventing post stroke cognitive impairment.

Post stroke dementia (PSD) develops in up to 40% of patients and often co-exists with Alzheimers disease in the elderly. Unsurprisingly, the combination of stroke and dementia is associated with considerable morbidity and mortality, and is devastating to patients and carers. Limited trial evidence suggests that lowering high blood pressure reduces the development of cognitive decline, vascular dementia and PSD, although whether this relates to the magnitude of BP reduction or specific drug classes remains unclear. Biological plausibility and/or existing studies suggest that other types of drug treatments might also be effective, including choline esterase inhibitors, lipid lowering agents, antiplatelet agents, and selective serotonin reuptake inhibitors. Preventing cognitive decline and dementia post stroke is critical and large definitive trials are now needed.

The influence of stroke risk factors and comorbidities on assessment of stroke therapies in humans and animals

The main driving force behind the assessment of novel pharmacological agents in animal models of stroke is to deliver new drugs to treat the human disease rather than to increase knowledge of stroke pathophysiology. There are numerous animal models of the ischaemic process and it appears that the same processes operate in humans. Yet, despite these similarities, the drugs that appear effective in animal models have not worked in clinical trials. To date, tissue plasminogen activator is the only drug that has been successfully used at the bedside in hyperacute stroke management. Several reasons have been put forth to explain this, but the failure to consider comorbidities and risk factors common in older people is an important one. In this article, we review the impact of the risk factors most studied in animal models of acute stroke and highlight the parallels with human stroke, and, where possible, their influence on evaluation of therapeutic strategies.

Determining the feasibility of ambulance-based randomised controlled trials in patients with ultra-acute stroke: Study protocol for the “Rapid Intervention with GTN in Hypertensive Stroke Trial” (RIGHT, ISRCTN66434824)

Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

Views of Paramedics on Their Role in an Out-of-Hospital Ambulance-Based Trial in Ultra-Acute Stroke: Qualitative Data From the Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT)

STUDY OBJECTIVE Optimal practices for recruiting, consenting, and randomizing patients, and delivering treatment in out-of-hospital ultra-acute stroke trials, remain unclear. We aim to identify key barriers and facilitators relevant to the design and conduct of ambulance-based stroke trials and to formulate preliminary recommendations for the design of future trials. METHODS Using semistructured interviews, we investigated the experiences and challenges faced by paramedics who took part in a randomized controlled trial in suspected ultra-acute stroke, the Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT), in which recruitment, consent, randomization, assessment, and treatment were delivered by paramedics before hospitalization. RESULTS We purposively selected a diversity sample of 14 of the 78 paramedics who participated in RIGHT. We identified 13 themes (7 facilitators and 6 barriers to out-of-hospital stroke research). A simple stroke diagnostic tool, use of proxy consent on behalf of patients, and straightforward trial processes were identified as the main facilitators. Recruitment became easier with each new randomization attempt. Key barriers reported were informed consent in the emergency setting, lack of institutional support for research, learning curve and rarity (each paramedic treats only a few eligible patients), and difficulty in attending training sessions. Interviewed paramedics were motivated to participate in research. CONCLUSION Ultra-acute stroke research in the out-of-hospital environment is feasible, but important barriers need to be addressed. Proxy consent by paramedics addresses some of the difficulties with the consent process in the out-of-hospital setting.

Intensive versus guideline blood pressure and lipid lowering in patients with previous stroke: main results from the pilot ‘Prevention Of Decline in Cognition After Stroke Trial’ (PODCAST) randomised controlled trial

Background Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. Methods In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125–170 mmHg were assigned randomly to at least 6 months of intensive (target SBP <125 mmHg) or guideline (target SBP <140 mmHg) BP lowering. The subset of patients with ischaemic stroke and total cholesterol 3.0–8.0 mmol/l were also assigned randomly to intensive (target LDL-cholesterol <1.3 mmol/l) or guideline (target LDL-c <3.0 mmol/l) lipid lowering. The primary outcome was the Addenbrooke’s Cognitive Examination-Revised (ACE-R). Results We enrolled 83 patients, mean age 74.0 (6.8) years, and median 4.5 months after stroke. The median follow-up was 24 months (range 1–48). Mean BP was significantly reduced with intensive compared to guideline treatment (difference –10·6/–5·5 mmHg; p<0·01), as was total/LDL-cholesterol with intensive lipid lowering compared to guideline (difference –0·54/–0·44 mmol/l; p<0·01). The ACE-R score during treatment did not differ for either treatment comparison; mean difference for BP lowering -3.6 (95% CI -9.7 to 2.4), and lipid lowering 4.4 (95% CI -2.1 to 10.9). However, intensive lipid lowering therapy was significantly associated with improved scores for ACE-R at 6 months, trail making A, modified Rankin Scale and Euro-Qol Visual Analogue Scale. There was no difference in rates of dementia or serious adverse events for either comparison. Conclusion In patients with recent stroke and normal cognition, intensive BP and lipid lowering were feasible and safe, but did not alter cognition over two years. The association between intensive lipid lowering and improved scores for some secondary outcomes suggests further trials are warranted. Trial Registration ISRCTN ISRCTN85562386

Effect of the neutral CLOTS 1 trial on the use of graduated compression stockings in the Efficacy of Nitric Oxide Stroke (ENOS) trial

Background and purpose Current evidence suggests that the time lag from the publication of randomised clinical trial results to changes in prescribing behaviour for drugs is gradually reducing. However, the effect of results of clinical trials of devices and non-pharmacological interventions on clinical practice is less clear. Methods Prospective data from the ongoing international ‘Efficacy of Nitric Oxide Stroke’ (ENOS) trial were analysed to assess the use of graduated compression stockings (GCS) for deep vein thrombus (DVT) prophylaxis in acute stroke patients before and after publication of the large ‘Clots in Legs Or sTockings after Stroke’ (CLOTS-1) trial. Results Data on GCS use were available for 1971 patients with acute stroke enrolled into ENOS from February 2003 to April 2011; of these, 498 (25.3%) wore GCS. Prior to publication of CLOTS-1, GCS use was common (>50%) in the UK, Australasia and Canada but infrequent in Asia and the rest of Europe. After publication of CLOTS-1, use of GCS in the UK declined from 398/656 (61%) to 20/567 (4%) (p<0.001) but not elsewhere (eg, in Australasia (57% before publication vs 70% after publication, p=0.24, but based on small numbers). Practice change was apparent within 3 months of the study publication and was sustained thereafter. There was no change in DVT rates before and after CLOTS-1 (0.8% vs 1.0%). Conclusions GCS use declined dramatically following the reporting of the CLOTS-1 trial. The results support the notion that a neutral trial of a device can influence clinical practice rapidly, which is important with a widely used and moderately expensive (time and finance) intervention.

Hemostasis and Vascular Dementia

Vascular dementia (VaD) comprises a group of syndromes caused by vascular lesions in the brain. Cognitive impairment may follow a single cortical or lacunar infarct in a strategic area of the brain, multiple infarcts, small-vessel disease (leukoaraiosis), intracerebral hemorrhage, or any of these conditions coexisting with Alzheimer dementia (so-called mixed dementia). Depending on case mix and the type of observational study, 10% of patients already have dementia before their first stroke, 10% develop it soon after their first stroke, and more than 33% have dementia after a recurrent stroke.1 Typically, dementia develops at a rate of 3% per year after stroke, and it is the stroke, rather than its underlying risk factors, that appears to be the dominant cause of subsequent dementia.1 See accompanying articles on pages 599 and 605 Although VaD, including poststroke dementia, is associated with conventional risk factors, such as hypertension and hypercholesterolemia,2,3 their relationship with hemostatic factors is less clear. This contrasts with the relationship between hemostatic factors and stroke, which is well established and involves both soluble (eg, fibrinogen4) and cellular (eg, mean platelet volume5) biomarkers. Several hemostatic factors, including fibrinogen and fibrin d-dimer levels, are associated with subsequent cognitive impairment and dementia in observational studies (Table).6–10 This issue of Arteriosclerosis, Thrombosis, and Vascular Biology expands on this relationship between “sticky blood” and cognition.11 Two new studies are described. View this table: Table. Selected Hemostatic Factors With …

The cog-4 subset of the national institutes of health stroke scale as a measure of cognition: relationship with baseline factors and functional outcome after stroke using data from the virtual international stroke trials archive.

Background. Assessing poststroke cognitive impairment is complex. A subscale of the NIHSS, the Cog-4, has been proposed as a quick test of “cognitive impairment.” but a study of its properties in a larger dataset is lacking. Methods. Data from 9,147 patients with acute stroke from the VISTA archive was used to generate Cog-4 scores. The statistical properties of Cog-4, its relationship with baseline clinical characteristics, and other functional outcome measures at day 90 were assessed. Results. Mean age of patients was 69.2 years and 45.8%, were females. Day-90 Cog-4 was highly positively skewed (skewness 0.926). Patients with left hemispheric stroke had higher day-90 Cog-4 score (P < 0.001). Age, stroke severity, and previous stroke were significant predictors of Cog-4. Cog-4 was significantly correlated with dependency (modified Rankin Scale, r s = 0.512), and disability (Barthel Index, r s = −0.493). Conclusions. The Cog-4 scale at day 90 cannot be considered a useful test of cognition since it only superficially measures cognition. It is heavily dependent on the side of stroke, is inevitably associated with functional outcome (being a subset of the NIHSS), and suffers from a profound “floor” effect. Specific and validated measures are more appropriate for the assessment of poststroke cognition than Cog-4.

Effect of Telmisartan on Cerebral and Systemic Haemodynamics in Patients with Recent Ischaemic Stroke: A Randomised Controlled Trial

High blood pressure (BP) is common in acute stroke and is independently associated with a poor outcome. Lowering BP might improve outcome if cerebral blood flow (CBF) is unaffected in the presence of dysfunctional autoregulation. We investigated the effect of telmisartan on systemic and cerebral haemodynamics in patients with recent stroke. Patients with ischaemic stroke (<5 days) were randomised to 90 days of telmisartan (80 mg) or placebo. CBF (primary outcome) was measured using xenon CT at baseline and 4 hours. BP and transcranial doppler (TCD) were performed at baseline, 4 hours after-treatment, and on days 4, 7, and 90. Cerebral perfusion pressure and zero filling pressure (ZFP) were calculated. Of a planned 24 patients, 17 were recruited. Telmisartan significantly accentuated the fall in systolic and diastolic BP over 90 days (treatment-time interaction , resp.) but did not alter BP at 4 hours after treatment (171/99 versus 167/87 mmHg), CBF, or CBF velocity. ZFP was significantly lower in the treatment group . Impairment at 7 days and dependency at 90 days did not differ between the groups. In this underpowered study, telmisartan did not significantly alter BP or CBF after the first dose. Telmisartan reduced BP over the subsequent 90 days and significantly lowered ZFP. This trial is registered with ISRCTN 41456162.