NXY-059: brain or vessel protection.
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Animals↗
Biomedical subjects
Kennedy Lees
Publications and source records attributed to Kennedy Lees.
The use of embolic signal detection in multicenter trials to evaluate antiplatelet efficacy: signal analysis and quality control mechanisms in the CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial.
BACKGROUND AND PURPOSE: The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial proved the effectiveness of the combination of clopidogrel and aspirin compared with aspirin alone in reducing presence and number of microembolic signals (MES) in patients with recently symptomatic carotid stenosis. The present study aimed at installing primary and secondary quality control measures in CARESS because MES evaluation relies on subjective judgment by human experts. METHODS: As primary quality control, centers participating in CARESS evaluated a reference digital audio tape (DAT) before the study containing both MES and artifacts. Interobserver agreement of classifying signals as MES was expressed as proportions of specific agreement of positive ratings (ps+/-values). For all DATs included in CARESS (n=300), online number of MES and off-line number of MES read by the central reader were compared using correlation coefficients. As secondary control, a sample of 16 of 300 DATs was cross-validated by another independent reader (post-trial validator). RESULTS: For the reference tape, the cumulative ps+/-value was 0.894 based on 12 of 14 observers. Two observers with very different results improved after a training procedure. Agreement between post-trial validator and central reader was ps+=0.805, indicating very good agreement. Correlation between online evaluation and off-line evaluation of DATs was very good overall (cumulative rho=0.84; P<0.001). CONCLUSIONS: Multicenter studies using MES as outcome parameter are feasible. However, primary and secondary quality control procedures are important.
Aspirin↗
Comparison of the effect of diuretics on carotid blood flow in stroke patients.
OBJECTIVES: Indapamide (IND) and bendroflumethiazide (BDZ) are both widely used in the management of blood pressure after stroke. There are theoretical reasons why these agents may differ with regard to their cardiovascular effects. We compared the effect of these agents on blood pressure and cerebral blood flow in a group of stroke patients. METHODS: In a prospective, randomized, double-blinded study we investigated the effect of 28 days' treatment with BDZ 2.5 mg od or IND 2.5 mg od on blood pressure and cerebral blood flow in a group patients with recent first-ever ischemic stroke. Using extracranial carotid and transcranial ultrasound we assessed carotid blood flow and intracranial hemodynamics. RESULTS: All data are expressed as mean (SD). Twenty-five patients completed the protocol (age 68.8 +/- 10.6 y). Groups I (IND) and B (BDZ) comprised 13 and 12 patients, respectively. Groups were well matched for demography and baseline characteristics. Percent change in mean arterial pressure reduction from baseline was (I = -14.7 +/- 12.5, P < 0.001 vs. B = -7.7 +/- 9.16 mm Hg, P = 0.02). There was a trend toward increased carotid blood flow in both groups (I = +10% +/- 47, P = 0.4 vs. B = +33% +/- 47, P = 0.12). No significant change in middle cerebral artery mean flow velocity or pulsatility index was observed. There was no significant difference between the 2 drugs with regard to change in blood pressure (95% confidence interval for difference -2.5 to 16.3 mm Hg, P = 0.14) or carotid blood flow (95% confidence interval for difference -58 to 27 mL/s, P = 0.45). CONCLUSIONS: Both diuretics reduced blood pressure to a similar and significant degree. There was no evidence of an adverse effect on cerebral blood flow or intracranial hemodynamics induced by either agent. No significant difference between the effect of IND and BDZ was observed.
Adult↗
Effect of perindopril on cerebral vasomotor reactivity in patients with lacunar infarction.
BACKGROUND AND PURPOSE: There is growing evidence that pharmacologic interference with the renin-angiotensin system may reduce risk of stroke, although the mechanism is unclear. Impaired reactivity of cerebral vessels has recently been recognized as a risk factor for stroke. We examined the effect of the angiotensin-converting enzyme (ACE) inhibitor perindopril on cerebral vasomotor reactivity to acetazolamide in patients with lacunar cerebral infarction. METHODS: We studied a cohort of male patients between 3 and 12 months after lacunar infarction confirmed on computed tomography. Each patient received perindopril 4 mg daily or matching placebo for 2 weeks in a randomized, double-blind, placebo-controlled crossover fashion. A 1-week washout period was observed between dosing periods. Cerebral vasomotor reactivity (increase in middle cerebral artery mean flow velocity in response to intravenous injection of 15 mg/kg acetazolamide) was measured before and after each dosing period using standard Doppler ultrasound techniques. RESULTS: Twelve patients (mean age 63.2+/-2.3 years) completed the protocol. There was no treatment order effect. Cerebral vasomotor reactivity was significantly greater after perindopril treatment (percent change from baseline +18.8+/-10.1% after perindopril, -4.6+/-4.1% after placebo; P=0.032). Dosing with perindopril did not affect resting cerebral blood flow velocity (percent change from baseline +3.1+/-9.5% after perindopril, -0.6+/-5.4% after placebo), nor was there a change in resting blood pressure (+1.8 mm Hg+/-3.1 after perindopril, +1.4 mm Hg+/-2.5 after placebo). CONCLUSIONS: This study provides evidence of a significant improvement in cerebral vasomotor reactivity induced by perindopril, beyond any effect on blood pressure. The results suggest a possible mechanism for the beneficial effect of ACE inhibition on stroke risk observed in recent clinical trials, and suggest a role for the renin-angiotensin axis in the pathophysiology of subcortical small vessel disease.
Acetazolamide↗
Acute treatment of ischaemic stroke. European Stroke Initiative.
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Acute Disease↗
Design of the Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial.
The Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial is a multicentre,randomised, placebo-controlled trial of magnesium sulphate (MgSO4) funded by the UK Medical Research Council. When complete, it will be the largest single neuroprotective study undertaken to date. Conscious patients presenting within 12 h of acute stroke with limb weakness are eligible. The primary outcome measure is combined death and disability as measured using the Barthel Index at 90-day follow up. By randomizing 2700 patients, the study will have 84% power to detect a 5.5% absolute reduction in the primary end-point. By April 2000, 86 centres were participating, with representation in Canada, USA, Europe, South America, Singapore and Australia. So far, 1206 patients have been randomised, of whom 37% were treated within 6 h. Overall 3-month mortality was 20% and the primary outcome event rate was 43%. The study is ongoing and centres worldwide are encouraged to participate.
Journal Article↗