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Biomedical subjects

David G Sherman

Publications and source records attributed to David G Sherman.

8 recordsLinked to original sources
PubMed2006

Safety and tolerability of arundic acid in acute ischemic stroke.

Arundic acid (AA; ONO-2506), a novel modulator of astrocyte activation, may improve neuronal survival after stroke. We conducted a multicenter, dose-escalating, randomized, double-blind Phase I trial of AA in acute ischemic stroke. Subjects were randomized to treatment with AA or placebo in sequential dose tiers of 2-12 mg/kg/h (10-16 patients/group) within 24 h of stroke onset. Study drug was infused for 1 h daily over 7 days, and follow-up terminated at 40 days. Neurological and functional outcomes were evaluated through Day 40 as exploratory endpoints. A total of 92 subjects were enrolled with no dose-related pattern of serious adverse events (AEs). Premature terminations caused by AEs occurred in four (8.2%) patients treated with AA and five (11.6%) treated with placebo. Two subjects treated with AA (4.1%) and four given placebo (9.3%) died. Exploratory efficacy analysis showed a trend toward improvement in the change from baseline National Institutes of Health Stroke Scale (NIHSS) in the 8 mg/kg/h AA group on Days 3 (p=0.023 vs. placebo), 7 (p=0.002), 10 (p=0.003), and 40 (p=0.018). A dose of 8 mg/kg/h AA produced a favorable trend in reduction of NIHSS that should be confirmed in a future clinical trial.

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PubMed2005

Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy.

OBJECTIVES: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) functional status substudy aimed to test the hypothesis that functional status is similar in rate-control and rhythm-control strategies. BACKGROUND: Randomized studies, including the AFFIRM study, have failed to demonstrate survival benefits between rate-control and rhythm-control strategies for atrial fibrillation (AF). However, AF may cause functional capacity or cognitive impairment that might justify maintenance of sinus rhythm. METHODS: Investigators of the AFFIRM study enrolled 4,060 patients with AF who required long-term therapy and who were 65 years of age or older or who had another risk factor for stroke or death. New York Heart Association functional class (NYHA-FC) and Canadian Cardiovascular Society Angina Classification were assessed at initial and each follow-up visit. From 22 randomly chosen functional status substudy sites, 245 participants underwent 6-min walk tests and Mini-Mental State Examination (MMSE) at initial, two-month, and yearly visits. Patients were assigned randomly to rate-controlling drugs, allowing AF to persist, or rhythm-controlling antiarrhythmic drugs, to maintain sinus rhythm. RESULTS: The NYHA-FC worsened with time in both rate-control and rhythm-control groups, with no differences between groups. Presence of AF was associated with worse NYHA-FC (p < 0.0001). No differences were observed in Canadian Cardiovascular Society Angina Classification or MMSE scores. Six-minute walk distance improved over time in both study arms. On average, walk distance was 94 feet greater in the rhythm-control group (adjusted p = 0.049). CONCLUSIONS: Modest improvement in 6-min walk distance was noted in the rhythm-control arm. Presence of AF was associated with worse NYHA-FC. No difference in cognitive function was detected.

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PubMed2005

Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study.

BACKGROUND: Atrial fibrillation (AF) is a risk factor for stroke, especially when accompanied by other high-risk cardiovascular predictors. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study was a multicenter comparison of high-risk patients with AF who were randomized to either a sinus rhythm control or a rate control strategy. METHODS: Physicians were encouraged to continue anticoagulation therapy for their patients. Patients in the sinus rhythm control group could stop warfarin sodium therapy after 4 (preferably a minimum of 12) weeks if they maintained sinus rhythm while receiving an antiarrhythmic drug. RESULTS: The AFFIRM Study enrolled 4060 patients. Mortality was the same in both groups. Two hundred eleven patients (8.2%) had a stroke event. Ischemic stroke occurred in 157 patients (6.3%), primary intraparenchymal hemorrhage in 34 (1.2%), and subdural or subarachnoid hemorrhage in 24 (0.8%). The most frequently determined ischemic stroke mechanism was cardioembolic (35/71 [49%]). Treatment assignment had no significant effect on the occurrence of ischemic stroke. Patients in AF at the time of the stroke event had a 60% greater chance of having an ischemic stroke, and those taking warfarin at the time of follow-up had a 69% decrease in the risk of having an ischemic stroke. CONCLUSIONS: In the AFFIRM Study, stroke rates were not significantly different in the rate control and sinus rhythm control arms. However, several clinical and therapeutic variables were associated with stroke risk. In patients with a history of AF at high risk for stroke or death, the presence of AF increases the risk of having a stroke, and warfarin therapy reduces the risk of having a stroke. The beneficial effect of warfarin therapy is seen not only in patients in AF but also in patients with a history of AF but who presumably remain in sinus rhythm.

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PubMed2004

Antithrombotic and hypofibrinogenetic therapy in acute ischemic stroke: what is the next step?

A thrombus occluding a brain artery is the leading mechanism underlying ischemic stroke. In the light of this pathophysiology, antithrombotic therapies have been among the most widely studied and used in the management of patients with ischemic stroke. Aspirin has a significant but modest benefit by reducing recurrent ischemic stroke and death given within 48 h of stroke onset. The use of anticoagulants including heparin, low molecular weight heparin, and heparinoids has not been supported by results of randomized clinical trials. Any reductions in ischemic stroke recurrence were offset by an increase in major bleeding. However, acute anticoagulation is widely used in specific disorders, including patients with high-risk cardiac sources of embolus, arterial dissection, venous sinus thrombosis, and hypercoagulable states. Early recurrent ischemic strokes in patients with atrial fibrillation and acute ischemic stroke have not been shown to be reduced with the heparins, when the effects of major bleeding and hemorrhagic worsening are considered. Recent clinical trials have suggested that other antithrombotic agents may be beneficial in acute ischemic stroke. Two such agents are ancrod and abciximab. Abciximab is currently being investigated in a large randomized clinical trial.

Acute Disease↗
PubMed2003

Lessons from the Stroke Prevention in Atrial Fibrillation trials.

Atrial fibrillation predisposes to left atrial thrombus formation and carries a sixfold increased risk for stroke. Antithrombotic therapies are the mainstay for stroke prevention. The National Institute of Neurological Disorders and Stroke-sponsored Stroke Prevention in Atrial Fibrillation (SPAF) studies assessed the value of warfarin, aspirin, and their combination for preventing stroke in six multicenter trials involving 3950 participants. This review presents the major results and implications, which offer unique perspectives on antithrombotic therapies for stroke prevention in atrial fibrillation. Warfarin and aspirin reduce stroke. Anticoagulation substantially benefits high-risk patients with atrial fibrillation, while many younger patients with atrial fibrillation have a low stroke rate when given aspirin. Pathogenetic and transesophageal echocardiographic correlations shed light on mechanisms by which antithrombotic agents prevent stroke. Warfarin inhibits formation of atrial appendage thrombi and markedly reduces cardioembolic strokes, while aspirin primarily prevents smaller, noncardioembolic strokes. The SPAF III stroke risk stratification scheme has been validated for identifying patients with high versus moderate versus low risk for stroke. Women with atrial fibrillation benefit from anticoagulation significantly more than men do. Many elderly patients with recurrent paroxysmal atrial fibrillation have high rates of stroke. Antithrombotic prophylaxis should be individualized on the basis of the estimated risk for stroke during aspirin therapy and the risk for bleeding during anticoagulation. Overall, nearly one third of patients with atrial fibrillation are low risk and should be treated with aspirin, and about one third are high risk and should receive warfarin if it can be given safely. For patients at moderate risk for stroke, patient preferences and access to reliable anticoagulation monitoring are particularly relevant.

Anticoagulants↗
PubMed2002

Ancrod.

Ischaemic stroke occurs in over 500,000 US residents each year. Most strokes are due to embolic or thrombotic occlusion of an artery to the brain. Strategies to reduce thrombus formation and to improve blood flow in the compromised arterial bed have been have been a major focus of management with the goal of improving the outcome of ischaemic stroke. Ancrod is a biological agent extracted from the venom of the Malayan pit viper that reduces blood fibrinogen levels. This action prolongs blood clot formation and lowers blood viscosity. Ancrod has been studied in a variety of ischaemic conditions including stroke. The clinical studies of ancrod in patients with stroke have shown a benefit with ancrod treatment in neurological outcome with only a modest increase in bleeding risk.

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