The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison.

BACKGROUND: Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke. METHODS: 1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6-14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke > or =14, less severe stroke <14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805. FINDINGS: In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10.5 days (SD 3.2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0.57, 95% CI 0.44-0.76, p=0.0001; difference -7.9%, -11.6 to -4.2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0.0036) or less than 14 (42 [8%] vs 69 [14%]; p=0.0044). The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; p=0.83). The frequency of the composite of symptomatic intracranial and major extracranial haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0.23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0.55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0.015). INTERPRETATION: Our results suggest that for patients with acute ischaemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration.

Stroke prevention in atrial fibrillation: pharmacological rate versus rhythm control.

Atrial fibrillation is a common arrhythmia associated with increased risk for embolic stroke. Restoration of sinus rhythm in patients with atrial fibrillation is a logical strategy to prevent the cardiovascular and thromboembolic complications of this dysrhythmia. The most common strategy for restoration of sinus rhythm is pharmacological antiarrhythmic therapy with or without electrical cardioversion. Five randomized clinical trials compared rhythm to rate-control strategies in patients with atrial fibrillation. These trials examined mortality, thromboembolic complications, exercise tolerance, quality of life, hospital admissions and drug-related adverse reactions. Mortality ranged from 2.9% to 23.8% among the trial subjects randomized to rhythm control versus 1.0% to 21.3% in the rate control subjects. The risk of thromboemboli was greater: 2.9% to 7.9% in the rhythm-control subjects compared with 0% to 5.5% in the rate control subjects. Hospital admissions and drug-related adverse events were increased in the rhythm-control subjects. Stroke and systemic emboli occurred more often in the rhythm-control subjects many of whom had been withdrawn from anticoagulation. Rhythm-control offered no advantage compared with rate control for patients with atrial fibrillation at increased risk for stroke. One explanation for this finding is that those patients thought to have been successfully converted to sinus rhythm in fact had asymptomatic paroxysmal episodes of atrial fibrillation increasing their risk of stroke because they were unprotected by anticoagulation. Pharmacological attempts to restore atrial fibrillation to sinus rhythm do not improve mortality or reduce thromboembolic events. All patients with atrial fibrillation at increased risk for stroke should be continued on long-term anticoagulation even if they appear to have been successfully restored to sinus rhythm.

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.

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.

Prevention of venous thromboembolism, recurrent stroke, and other vascular events after acute ischemic stroke: the role of low-molecular-weight heparin and antiplatelet therapy.

Patients with stroke or transient ischemic attacks (TIAs) are at increased risk of vascular events, such as recurrent stroke or venous thromboembolism (VTE), and thus the secondary prevention of such events is an important element of managing these patients. Current guidelines recommend that patients with acute stroke, restricted mobility, and no contraindications to anticoagulants receive thromboprophylactic therapy with low-dose unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or heparinoids to prevent VTE. This recommendation is based on clinical trial evidence that UFH is effective in reducing the incidence of deep vein thrombosis (DVT) after stroke. LMWHs have been shown to be at least as effective as UFH in preventing VTE, and offer advantages in terms of a more predictable anticoagulant effect, lower risk of bleeding, and ease of administration. However, adequately powered trials are needed to confirm their relative benefits and risks; the Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study with enoxaparin, currently in progress, should provide valuable information in this context. Antiplatelet therapy has been shown to be effective in preventing recurrent vascular events, as evidenced by the results of studies such as the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial. In contrast, evidence for the efficacy of LMWH in this situation is contradictory. Given the potential benefits of LMWH in preventing VTE in stroke patients, a potential rationale exists for combination therapy with antiplatelet agents and LMWHs. Clinical trials with such combinations are warranted.

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.

Enoxaparin versus unfractionated heparin in the prevention of venous thromboembolism after acute ischemic stroke: rationale, design, and methods of an open-label, randomized, parallel-group multicenter trial.

BACKGROUND: Small sample size and methodologic limitations make it difficult to interpret and compare trials of low molecular-weight heparin (for example, enoxaparin) versus unfractionated heparin as prophylactic treatment for venous thromboembolism (VTE), that is, deep vein thrombosis and/or pulmonary embolism, in patients with acute ischemic stroke. This prospective, open-label, randomized, parallel-group, multicenter trial is designed to evaluate the efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of VTE after acute ischemic stroke. METHODS: Approximately 1760 patients with the diagnosis of acute ischemic stroke accompanied by leg paralysis will be randomly assigned (1:1) within 48 hours of stroke symptoms to receive enoxaparin (40 mg subcutaneously) once daily or unfractionated heparin (5000 U subcutaneously) every 12 hours for 10 +/- 4 days. Contrast venography will be used to evaluate asymptomatic patients after treatment for deep vein thrombosis. In addition, diagnostic algorithms will be used to objectively confirm or rule out VTE events for patients in whom upper- or lower-extremity deep vein thrombosis/pulmonary embolism is suggested. RESULTS: The primary efficacy end point measure will be the cumulative occurrence of documented VTE during the initial treatment period. Secondary end points are VTE incidence; neurologic outcome at days 30, 60, and 90; safety; and health care resource use during initial hospitalization and during the 30- and 90-day follow-up periods. CONCLUSIONS: This study will provide clinical and health economic data regarding the use of enoxaparin as primary prophylactic treatment of VTE in patients who have had an acute ischemic stroke.

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.

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.

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.