A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility.

BACKGROUND: Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke. METHODOLOGY/PRINCIPAL FINDINGS: A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01). CONCLUSIONS/SIGNIFICANCE: Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN83673558.

Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092).

BACKGROUND AND PURPOSE: Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony-stimulating factor (G-CSF) after stroke and its effect on circulating CD34+ stem cells. METHODS: We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 microg/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34+ stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. RESULTS: Thirty-six patients, whose mean+/-SD age was 76+/-8 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 microg/kg) increased CD34+ count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P=0.005). A dose-dependent rise in white cell count (P<0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. CONCLUSIONS: G-CSF is effective at mobilizing bone marrow CD34+ stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined.

Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke.

High blood pressure (BP), pulse pressure (PP), and rate pressure product (RPP) are each associated independently with a poor outcome in acute ischemic stroke. Whereas nitric oxide (NO) donors, such as glyceryl trinitrate (GTN), lower blood pressure in acute ischemic stroke, their effect on other hemodynamic measures is not known. We performed a systematic review of the effects of NO donors on systemic hemodynamic measures in patients with acute/subacute stroke. Randomized controlled trials were identified from searches of the Cochrane Library, Pubmed, and Embase. Information on hemodynamic measures, including systolic BP (SBP), diastolic BP (DBP), and heart rate, were assessed, and hemodynamic derivatives of these were calculated: PP (PP = SBP - DBP), mean arterial pressure (MAP = DBP + PP/3), mid blood pressure (MBP = (SBP + DBP)/2), pulse pressure index (PPI = PP/MAP), and RPP (RPP = SBP x HR). The effect of treatment on hemodynamic measures was calculated as the weighted mean difference (WMD) between treated and control groups with adjustment for baseline. Three trials involving 145 patients were identified; 93 patients received the NO donor, GTN, and 52 patients composed the control group. Compared with placebo, GTN significantly reduced SBP (WMD, -9.80 mm Hg; P < .001), DBP (WMD, -4.43 mm Hg; P < .001), MAP (WMD, - 6.41 mm Hg; P < .001), MBP (WMD, -7.33 mm Hg; P < .001), PP (WMD, -6.11 mm Hg; P < .001), and PPI (WMD, -0.03; P = .04). GTN increased HR (WMD, +3.87 bpm; P < .001) and lowered RPP insignificantly (WMD, -323 mm Hg.bpm; P = .14). Our findings indicate that the NO donor GTN reduces BP, PP, and other derivatives in acute and subacute stroke while increasing HR.