Philip M.W. Bath

Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack 2008

This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

BACKGROUND Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Blood Pressure and Clinical Outcomes in the International Stroke Trial

Background and Purpose— Among patients with acute stroke, high blood pressure is often associated with poor outcome, although the reason is unclear. We analyzed data from the International Stroke Trial (IST) to explore the relationship between systolic blood pressure (SBP), subsequent clinical events over the next 2 weeks, and functional outcome at 6 months in patients with acute stroke. Methods— We included in the analysis 17 398 patients from IST with confirmed ischemic stroke. A single measurement of SBP was made immediately before randomization. Clinical events within 14 days of randomization were recorded: recurrent ischemic stroke, symptomatic intracranial hemorrhage, death resulting from presumed cerebral edema, fatal coronary heart disease, and death. Survival and dependency were assessed at 6 months. Outcomes were adjusted for age, sex, clinical stroke syndrome, time to randomization, consciousness level, atrial fibrillation, and treatment allocation (aspirin, unfractionated heparin, both, or neither). Results— A U-shaped relationship was found between baseline SBP and both early death and late death or dependency: early death increased by 17.9% for every 10 mm Hg below 150 mm Hg (P <0.0001) and by 3.8% for every 10 mm Hg above 150 mm Hg (P =0.016). The rate of recurrent ischemic stroke within 14 days increased by 4.2% for every 10–mm Hg increase in SBP (P =0.023); this association was present in both fatal and nonfatal recurrence. Death resulting from presumed cerebral edema was independently associated with high SBP (P =0.004). No relationship between symptomatic intracranial hemorrhage and SBP was seen. Low SBP was associated with a severe clinical stroke (total anterior circulation syndrome) and an excess of deaths from coronary heart disease (P =0.002). Conclusions— Both high blood pressure and low blood pressure were independent prognostic factors for poor outcome, relationships that appear to be mediated in part by increased rates of early recurrence and death resulting from presumed cerebral edema in patients with high blood pressure and increased coronary heart disease events in those with low blood pressure. The occurrence of symptomatic intracranial hemorrhage within 14 days was independent of SBP.

Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events

BACKGROUND Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Platelet size: measurement, physiology and vascular disease.

Platelet volume is a marker of platelet function and activation. It is readily measured as mean platelet volume (MPV) by clinical haematology analysers using sodium citrate as the anticoagulant. Measurement in EDTA can be unreliable since MPV increases significantly in a time-dependent manner. MPV correlates with platelet function and activation, whether measured as aggregation, thromboxane synthesis, beta-thromboglobulin release, procoagulant function, or adhesion molecule expression. MPV is increased in certain vascular risk factor states, including hypercholesterolaemia and diabetes mellitus, but not essential hypertension. It is increased in acute myocardial infarction, acute ischaemic stroke, pre-eclampsia and renal artery stenosis. Importantly, an elevated MPV predicts a poor outcome following myocardial infarction, restenosis following coronary angioplasty, and the development of pre-eclampsia. Research into the epidemiology of MPV is now required to determine whether thrombomegaly is a risk factor for developing vascular disease. Similarly, the physiological mechanisms which regulate MPV within the megakaryocyte need to be elucidated. Whether MPV ever becomes a routinely requested test remains to be seen but changes in methodology will be required first.

Blood Pressure Reduction and Secondary Prevention of Stroke and Other Vascular Events: A Systematic Review

Background— High blood pressure is a risk factor for stroke recurrence. We assessed the effectiveness of lowering blood pressure in preventing recurrent vascular events in patients with previous stroke or transient ischemic attack. Summary of Review— We performed a systematic review and meta-regression of completed randomized controlled trials that investigated the effect of lowering blood pressure on recurrent vascular events in patients with prior ischemic or hemorrhagic stroke or transient ischemic attack. Trials were identified from searches of 3 electronic databases (Cochrane Library, EMBASE, MEDLINE). Seven randomized controlled trials, with 8 comparison groups, were included. Lowering blood pressure or treating hypertension with a variety of antihypertensive agents reduced stroke (odds ratio [OR], 0.76; 95% CI, 0.63 to 0.92), nonfatal stroke (OR, 0.79; 95% CI, 0.65 to 0.95), myocardial infarction (OR, 0.79; 95% CI, 0.63 to 0.98), and total vascular events (OR, 0.79; 95% CI, 0.66 to 0.95). No effect was seen on vascular or all-cause mortality. Heterogeneity was present for several outcomes and was partly related to the class of antihypertensive drugs used; angiotensin-converting enzyme inhibitors and diuretics separately, and especially together, reduced vascular events, while &bgr;-receptor antagonists had no discernable effect. The reduction in stroke was related to the difference in systolic blood pressure between treatment and control groups (P =0.002). Conclusions— Evidence from randomized controlled trials supports the use of antihypertensive agents in lowering blood pressure for the prevention of vascular events in patients with previous stroke or transient ischemic attack. Vascular prevention is associated positively with the magnitude by which blood pressure is reduced.

High Blood Pressure in Acute Stroke and Subsequent Outcome. A Systematic Review

Abstract—High blood pressure (BP) is common in acute stroke and might be associated with a poor outcome, although observational studies have given varying results. In a systematic review, articles were sought that reported both admission BP and outcome (death, death or dependency, death or deterioration, stroke recurrence, and hematoma expansion) in acute stroke. Data were analyzed by the Cochrane Review Manager software and are given as odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). Altogether, 32 studies were identified involving 10 892 patients. When all data were included, death was significantly associated with an elevated mean arterial BP ([MABP] OR, 1.61; 95% CI, 1.12 to 2.31) and a high diastolic BP ([DBP] OR, 1.71; 95% CI, 1.33 to 2.48). Combined death or dependency was associated with high systolic BP ([SBP] OR, 2.69; 95% CI, 1.13 to 6.40) and DBP (OR, 4.68; 95% CI, 1.87 to 11.70) in primary intracerebral hemorrhage (PICH). Similarly, high SBP (+11.73 mm Hg; 95% CI, 1.30 to 22.16), MABP (+9.00 mm Hg; 95% CI, 0.92 to 17.08), and DBP (+6.00 mm Hg; 95% CI, 0.19 to 11.81) were associated with death or dependency in ischemic stroke. Combined death or deterioration was associated with a high SBP (OR, 5.57; 95% CI, 1.42 to 21.86) in patients with PICH. In summary, high BP in acute ischemic stroke or PICH is associated with subsequent death, death or dependency, and death or deterioration. Moderate lowering of BP might improve outcome. Acute BP lowering needs to be tested in 1 or more large, randomized trials.

Influence of platelet size on outcome after myocardial infarction

Although platelet characteristics have an important influence on ischaemic heart disease, the nature of the association of platelet size and platelet count with death and reinfarction after an index heart attack is unknown. Mean platelet volume (MPV), a determinant of platelet reactivity, was measured in 1716 men six months after myocardial infarction (MI). Deaths and recurrent ischaemic heart disease events were then assessed at two years. MPV was greater in 126 men who had a further ischaemic event (fatal or non-fatal) than in the 1590 men who had no further MI (p less than 0.001). In addition, the MPV was larger in men who died than in those who did not (p less than 0.001). There was no difference in platelet count between these groups. When analysed by quartiles, consistent trends of increasing age-adjusted relative odds of death and recurrent ischaemic events were noted for MPV. MPV did not correlate with known ischaemic heart disease risk factors such as blood pressure, blood lipids, fibrinogen, white cell count, or plasma viscosity. We believe that MPV is a further independent risk factor for recurrent MI.

Publication Bias in Reports of Animal Stroke Studies Leads to Major Overstatement of Efficacy

Publication bias confounds attempts to use systematic reviews to assess the efficacy of various interventions tested in experiments modelling acute ischaemic stroke, leading to a 30% overstatement of efficacy of interventions tested in animals.

Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial

BACKGROUND Magnesium is neuroprotective in animal models of stroke, and findings of small clinical pilot trials suggest potential benefit in people. We aimed to test whether intravenous magnesium sulphate, given within 12 h of stroke onset, reduces death or disability at 90 days. METHODS 2589 patients were randomised within 12h of acute stroke to receive 16 mmol MgSO4 intravenously over 15 min and then 65 mmol over 24 h, or matching placebo. Primary outcome was a global endpoint statistic expressed as the common odds ratio for death or disability at day 90. Secondary outcomes were mortality and death or disability, variously defined as Barthel score less than 95, Barthel score less than 60, and modified Rankin scale more than 1. Predefined subgroup analyses were for the primary endpoint in patients in whom treatment commenced within 6 h versus after 6 h, ischaemic versus non-ischaemic strokes, and cortical stroke syndromes versus non-cortical strokes. Intention-to-treat and efficacy analyses were done. FINDINGS The efficacy dataset included 2386 patients. Primary outcome was not improved by magnesium (odds ratio 0.95, 95% CI 0.80-1.13, p=0.59). Mortality was slightly higher in the magnesium-treated group than in the placebo group (hazard ratio 1.18, 95% CI 0.97-1.42, p=0.098). Secondary outcomes did not show any treatment effect. Planned subgroup analyses showed benefit of magnesium in non-cortical strokes (p=0.011) whereas greater benefit had been expected in the cortical group. INTERPRETATION Magnesium given within 12 h of acute stroke does not reduce the chances of death or disability significantly, although it may be of benefit in lacunar strokes.