Amit K. Mistri

Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial

BACKGROUND Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for lowering blood pressure in patients who have had a stroke. METHODS Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure [SBP] >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008. FINDINGS 179 patients (mean age 74 [SD 11] years; SBP 181 [SD 16] mm Hg; diastolic blood pressure [DBP] 95 [SD 13] mm Hg; median National Institutes of Health stroke scale [NIHSS] score 9 [IQR 5-16] points) were randomly assigned to receive labetolol (n=58), lisinopril (n=58), or placebo (n=63) between January, 2005, and December, 2007. The primary outcome--death or dependency at 2 weeks--occurred in 61% (69) of the active and 59% (35) of the placebo group (relative risk [RR] 1.03, 95% CI 0.80-1.33; p=0.82). There was no evidence of early neurological deterioration with active treatment (RR 1.22, 0.33-4.54; p=0.76) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo (21 [17-25] mm Hg vs 11 [5-17] mm Hg; p=0.004). No increase in serious adverse events was reported with active treatment (RR 0.91, 0.69-1.12; p=0.50) but 3-month mortality was halved (9.7%vs 20.3%, hazard ratio [HR] 0.40, 95% CI 0.2-1.0; p=0.05). INTERPRETATION Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events. Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, in view of the small sample size, care must be taken when these results are interpreted and further evaluation in larger trials is needed.

Pressor Therapy in Acute Ischemic Stroke Systematic Review

Background and Purpose— Systolic blood pressure (SBP) levels below 140 mm Hg after acute stroke occur in 18% to 25% of patients, and may be associated with adverse outcome, in terms of death and disability. It has thus been proposed that BP elevation in acute ischemic stroke may be beneficial by increasing perfusion to the peri-infarct penumbra, though not only in those with low BP levels. Methods— All articles studying BP elevation in the context of acute stroke were identified using a structured search strategy. Results— Two reviewers independently searched the databases, and 12 relevant publications were identified. All identified publications related to acute ischemic stroke and no articles on pressor therapy in primary hemorrhagic stroke were found. The review included 319 subjects (age: 42 to 88 years, 46% male), with phenylephrine being the most commonly used pressor agent, though 8 studies incorporated volume expansion. Because of small numbers, and varying entry/outcome criteria, no meta-analysis of outcome measures was possible. Overall, in these few studies undertaken, pressor therapy in acute stroke appears feasible and well-tolerated. The benefit and risks in terms of clinical outcomes remains unknown, but intensive monitoring is advised if such therapy is undertaken. Conclusions— Theoretical arguments exist for inducing BP elevation in acute ischemic stroke to increase blood flow to the ischemic penumbra across patients with a broad BP range. To date, there have only been a few small trials with inconclusive results. Many questions are still unanswered about the safety and potential benefits of pressor therapy in acute stroke. Hopefully, ongoing trials will answer some of these important questions.

Controlling hypertension and hypotension immediately post stroke (CHHIPS)--a randomised controlled trial.

OBJECTIVES To assess the effects of acute pressor and depressor blood pressure (BP) manipulation on 2-week death and dependency following acute stroke and investigate the safety and efficacy of such treatments. DESIGN A multicentre, prospective, randomised, double-blind, placebo-controlled titrated-dose trial. SETTING Five hospitals in England. PARTICIPANTS Patients over 18 years admitted to hospital with a clinical diagnosis of suspected stroke and either (1) symptom onset < 36 hours and hypertension, defined as systolic BP (SBP) < 160 mmHg (depressor arm), or (2) symptom onset < 12 hours and hypotension, defined as SBP < or = 140 mmHg (pressor arm). INTERVENTIONS Patients were allocated to either the pressor or the depressor arm depending on blood pressure at randomisation. The ratio of allocation to active intervention versus matched placebo was 2:1 for the depressor arm and 1:1 for the pressor arm. MAIN OUTCOME MEASURES The primary end point was death and dependency at 2 weeks, with dependency defined as a modified Rankin score < 3. Secondary end points were the safety of acute pressor (0-12 hours post stroke) and depressor (0-36 hours post stroke) BP manipulation in stroke patients; whether effects of BP reduction are influenced by stroke type (ischaemic versus haemorrhagic); whether alternative routes for administration of antihypertensive therapy (including sublingual and intravenous) are effective in dysphagic stroke patients; whether effects of BP manipulation are influenced by the time to treatment; and the short- and medium-term cost-effectiveness of such therapy in the acute post-stroke period on subsequent disability or death. RESULTS 180 patients were recruited over the 36-month trial period, 179 in the depressor arm and one in the pressor arm (who received placebo). No significant difference was found in death or dependency at 2 weeks between those receiving active depressor treatment with lisinopril or labetalol and those receiving placebo, although numbers recruited to the trial were lower than projected. Active treatment was not associated with an increase in early neurological deterioration despite significantly greater reductions in BP at 24 hours and 2 weeks with active therapy compared with placebo. Active treatment was generally well tolerated and treatment discontinuation rates were similar in active and placebo groups. Survival analysis showed that the active treatment group had a lower mortality at 3 months than the placebo group (p = 0.05). The pressor arm was closed early because of problems with recruitment, so no conclusions can be drawn regarding this therapy. CONCLUSIONS Oral and sublingual lisinopril and oral and intravenous labetalol are effective BP-lowering agents in acute cerebral infarction and haemorrhage and do not increase the likelihood of early neurological deterioration. The study was not sufficiently powered to detect a difference in disability or death at 2 weeks. However, the 3-month difference in mortality in favour of active treatment is of interest, although care must be taken in interpretation of the results. Further work is needed to confirm this and to assess whether there are differences in the effectiveness of labetalol compared with lisinopril in terms of reducing death or dependency after acute stroke, and whether the introduction of treatment post stroke earlier than was achieved here would be of greater benefit.

Current status of statin therapy for stroke prevention.

Stroke is a leading cause of mortality and long-term disability in the Western world. Lipid abnormalities are a key risk factor for stroke, elevated LDL-cholesterol being the most common abnormality. No clear association has been demonstrated between elevated LDL-cholesterol and stroke incidence, possibly due to the lack of appropriate etiopathophysiological classification of stroke in most studies. Nonetheless, statin therapy is associated with significant reduction in first and recurrent stroke, and there remains a net benefit despite a significant but small increase in hemorrhagic stroke. Following a stroke, indirect evidence supports continuation of prestroke statin therapy while the impact of de novo statin therapy in acute stroke remains uncertain. International guidelines advise an objective assessment of cardiovascular risk to determine the appropriateness of statins for primary prevention and near universal use of statins for secondary prevention after the acute phase of ischemic stroke. There is lack of consensus with regard to the choice of agent, timing of initiation, dose and duration of therapy. Some guidelines advocate high-dose atorvastatin while others suggest the use of simvastatin owing to generic availability and low cost. While the benefits of preventive interventions for stroke are well established and clearly outlined in international guidelines, there is poor application of such measures in clinical practice. This article summarizes the current understanding of the role of statins in stroke prevention and early studies of potential interventions to overcome the barriers to effective statin therapy for secondary prevention. There is a clear need for further research into identifying deficiencies in long-term management, barriers to optimal secondary prevention and novel interventions to overcome these barriers.

Short-Term Blood Pressure Variability in Acute Stroke: Post Hoc Analysis of the Controlling Hypertension and Hypotension Immediately Post Stroke and Continue or Stop Post-Stroke Antihypertensives Collaborative Study Trials

Background and Purpose— Short-term blood pressure variability (BPV) may predict outcome in acute stroke. We undertook a post hoc analysis of data from 2 randomized controlled trials to determine the effect of short-term BPV on 2-week outcome. Methods— Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) was a trial of BP-lowering, enrolling 179 acute stroke patients (onset <36 hours). Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS) compared a strategy of continuation versus temporarily stopping prestroke antihypertensive therapy in 763 acute stroke patients (onset <48 hours). BPV at baseline (defined as SD, coefficient of variation, variation independent of the mean, and average real variability) was derived from standardized casual cuff BP measures (6 readings <30 minutes). Adjusted logistic regression models were used to assess the relation between BPV and death and disability (modified Rankin scale>3) at 2 weeks. Results— Seven hundred six (92.5%) and 171 (95.5%) participants were included in the analysis for the COSSACS and CHHIPS data sets, respectively. Adjusted logistic regression analyses revealed no statistically significant associations between any of the included BPV parameters with 2-week death or disability in either study data set: COSSACS, odds ratio SD systolic BP 0.98 (0.78–1.23); CHHIPS, odds ratio SD systolic BP 0.97 (0.90–1.11). Conclusions— When derived from casual cuff BP measures, short-term BPV is not a useful predictor of early (2 weeks) outcome after acute stroke. Differing methodology may account for the discordance with previous studies indicating long-term (casual BPV) and short-term (beat-to-beat BPV) prognostic value. Clinical Trial Registration— COSSACS was registered on the International Standard Randomised Controlled Trial Register; URL: http://www.isrctn.com. Unique identifier: ISRCTN89712435. CHHIPS was registered on the National Research Register; URL: http://public.ukcrn.org.uk. Unique identifier: N0484128008.

Thrombolysis in Acute Ischaemic Stroke: An Update

Stroke is a major cause of mortality and morbidity, and thrombolysis has served as a catalyst for major changes in the management of acute ischaemic stroke. Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved thrombolytic agent at present indicated for acute ischaemic stoke. While the licensed time window extends to 3 h from symptom onset, recent data suggest that the trial window can be extended up to 4.5 h with overall benefit. Nonetheless, ‘time is brain’ and every effort must be made to reduce the time delay to thrombolysis. Intracranial haemorrhage is the major complication associated with thrombolysis, and key factors increasing risk of haemorrhage include increasing age, high blood pressure, diabetes and stroke severity. Currently, there is no direct evidence to support thrombolysis in patients >80 years of age, with a few case series indicating no overt harm. Identification of viable penumbra based on computed tomography/magnetic resonance imaging may allow future extension of the time window. Adjuvant transcranial Doppler ultrasound has the potential to improve reperfusion rates. While intra-arterial thrombolysis has been in vogue for a few decades, there is no clear advantage over intravenous thrombolysis. The evidence base for thrombolysis in specific situations (e.g. dissection, pregnancy) is inadequate, and individualized decisions are needed, with a clear indication to the patient/carer about the lack of direct evidence, and the risk–benefit balance. Patient-friendly information leaflets may facilitate the process of consent for thrombolysis. This article summarizes the recent advances in thrombolysis for acute ischaemic stroke. Key questions faced by clinicians during the decision-making process are answered based on the evidence available.

Acute stroke hypertension: current and future management.

The management of hypertension in acute stroke remains a hotly debated issue. Clinical practice varies widely between physicians, and both European and US guidelines reflect the uncertainty surrounding this question. Although there is a large amount of data that, on the whole, tends to support a connection between poststroke hypertension and hypotension and worse outcome, there have been few randomized controlled trials to clarify whether pharmacologic intervention is safe or beneficial. Data from secondary prevention trials convincingly demonstrate the benefits of controlling hypertension after a stroke but do not guide us as to how early to implement therapy. There is even less information from trials regarding the use of pressor agents in hypotensive stroke patients. This review discusses the dilemmas in the management of acute stroke hypertension and summarizes the available evidence from studies involving a variety of both depressor and pressor agents. The authors detail the ongoing studies that will help to answer some of the outstanding questions and summarizes the existing guidelines regarding indications for acute stroke blood pressure manipulation currently available to physicians.

Current status of blood pressure management after stroke

Stroke is a leading cause of mortality and long-term disability in the western world, accounting for 5% of the UK health budget. Consequently, it has been the major focus of recent healthcare advances. Physiological disturbances are common following an acute stroke, chiefly blood pressure (BP) abnormalities (high and ‘relatively’ low BP), which indicate adverse prognosis. While pilot studies suggest that early intervention to moderate both extremes of BP may improve outcomes, definitive evidence is awaited from ongoing research. Long-term elevated BP is the most prevalent risk factor for future stroke, with a comprehensive evidence base supporting BP reduction to reduce the risk of vascular events, including stroke. However, adherence to secondary preventive medications, including antihypertensive agents, remains poor. This article summarizes the current understanding of the role of BP in stroke, focusing on the management of BP for secondary prevention. Further emphasis is placed on identifying deficiencies in long-term management; barriers to improved application and potential interventions to overcome these barriers are summarized.

Non-pharmacological management of urinary incontinence

Urinary incontinence is a common and under-reported symptom, affecting one in five people, with a higher prevalence in women and those who are elderly. It can have a major impact on physical health and social activity. Initial assessment to categorize symptom type is the key to guiding further therapy. Non-pharmacological (NP) options are preferred as first-line intervention, and if unsuccessful, are followed by anticholinergics, often in combination with NP options. Surgical intervention must be sought where appropriate. However, NP interventions are often not considered due to uncertainty about the evidence-base, perceived difficulty of application and perhaps a lack of awareness of or access to specialist continence services. This article addresses the first of the barriers, summarizing the evidence for various NP interventions, including lifestyle interventions, physical therapies, behavioural therapies and containment options, enabling the reader to formulate an evidence-based opinion and a pragmatic view on the feasibility, efficacy and applicability of the various NP interventions, without automatic recourse to anticholinergic medication in the first instance.

Continence aids in the management of urinary incontinence

Urinary incontinence is a common problem, more so in older people and those in residential or nursing homes. Guidelines promote a structure to the management of incontinence, recommending non-pharmacological measures (including continence aids) as first-line options. Anticholinergic medications are used widely for urge incontinence, and surgical measures employed in selective cases.Whilst other treatments are being tried, or where incontinence is refractory to treatment (about 30% of cases), it is important to promote continence or contain incontinence with continence aids in order to minimize psychological complications. What can be a bewildering array of aids is available and choosing the right type of aid requires knowledge of these. Here, we suggest a classification of continence aids, describing individual characteristics and appropriate situations for use.