Oscar Benavente

Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.

Nonvalvular atrial fibrillation is an important independent risk factor for stroke. Since 1989, 16 published clinical trials have conducted 36 separate randomized comparisons of antithrombotic agents in approximately 10 000 participants with atrial fibrillation (1-17). Previously published meta-analyses and pooled analyses of individual patient data (18-20) have considered, in various combinations, the first 6 clinical trials to be published. We present a meta-analysis of all currently available trials to further characterize the comparative efficacy and safety of antithrombotic therapy for the prevention of stroke in patients with atrial fibrillation. Methods Randomized trials testing long-term (>3 months) use of antithrombotic agents in patients with atrial fibrillation were sought by a computerized search of the OVID/MEDLINE databases (from 1966 to 1999, not restricted by language) and by inquiries to the Cochrane Collaboration Stroke Review Group and Antithrombotic Trialists Collaboration. Studies of atrial fibrillation associated with prosthetic cardiac valves or mitral stenosis were not considered; trials reporting results for subgroups of participants with atrial fibrillation among other participants without atrial fibrillation were included (14, 16). Double-blind and nonblinded trials were included, and sensitivity analysis was used to compare pooled results, as appropriate. We excluded one randomized trial in which results for participants with atrial fibrillation (approximately half of all participants) were not reported separately (21). We have anecdotal knowledge of two additional trials that are ongoing or have not been published (Table 1). Table 1. Randomized Clinical Trials for Nonvalvular Atrial Fibrillation Two reviewers independently extracted data from published sources on the number of patients treated, total follow-up exposure, and the occurrence of five outcomes by intention-to-treat analysis: all stroke (hemorrhagic and ischemic), ischemic stroke, intracranial hemorrhage, all-cause mortality, and major extracranial bleeding. The criteria for each of these outcomes were those used in each individual trial; major deviations are noted in footnotes to the tables. Intracranial hemorrhage included spontaneous and traumatic subdural hematomas. Transient ischemic attacks (TIAs) were not considered. The percentage of participants who underwent neuroimaging or autopsy to reliably distinguish between ischemic or hemorrhagic stroke varied, and this percentage was not always reported. Therefore, all stroke (hemorrhagic and ischemic) was chosen as the primary outcome. Effects of antithrombotic therapy on combinations of events (for example, stroke, myocardial infarction, or vascular death) and effects of age and sex were not consistently reported and are not considered here. Intention-to-treat results were used for the main analyses, but only results noted during treatment were available for one small trial that tested antiplatelet agents (14). Primary prevention refers to patients without previous stroke or TIA; secondary prevention refers to patients with previous stroke or TIA. Detailed consideration of the design and execution of individual trials can be found in our systematic reviews prepared for the Cochrane Collaboration Stroke Review Group (16, 22). The authors participated in the Stroke Prevention in Atrial Fibrillation (SPAF) I, II, and III clinical trials (1987 to 1999), which were funded by the National Institute of Neurologic Disorders and Stroke. Meta-analyses of the results of the trials are presented as relative risk reductions and absolute risk reductions for treatment groups compared with control groups. To estimate the relative risk reduction, the combined odds ratio was computed by using the modified Mantel-Haenszel (Peto) method (23), and the estimate was then subtracted from 1. For a study in which no events were observed for a specific outcome and treatment, 0.5 was added to the empty cell. The absolute risk reduction is a weighted estimate of the difference in annualized event rates (24). Before we estimated risk reduction, we tested the assumption of the statistical homogeneity of the treatment effect (across trials and within a specific scenario) by using the QL statistic for the relative odds scale (24) or the QW statistic with unequal weights for the absolute risk scale (24). Lack of homogeneity across trials precluded estimation of the treatment effect, as noted. Homogeneity was assessed for all meta-analyses of relative risk reduction and absolute risk reduction; the exact P value was reported for all main analyses and for analyses in which the P value was less than 0.2. Estimates of relative risk reduction in individual trials were computed by subtracting the estimated odds ratio from 1. We estimated absolute risk reductions in individual trials by calculating the absolute difference in annualized event rates (events per person-years of observation). A P value less than 0.05 was considered statistically significant; all tests and CIs are two-sided. Calculations were done by using SPSS software (SPSS, Inc., Chicago, Illinois) and EGRET software (Cytel Software Corp., Cambridge, Massachusetts). Results Sixteen randomized trials published between 1989 and 1999 included 9874 participants with nonvalvular atrial fibrillation, with 2239 participants assigned to placebo (Table 1) (1-16). Total reported exposure was about 16 400 person-years (mean follow-up, 1.7 years). Fourteen trials included only participants with atrial fibrillation (1-13, 15); 2 trials included participants with atrial fibrillation in larger trials of secondary stroke prevention (14, 16). Warfarin was used exclusively in 10 trials testing oral anticoagulant agents; other derivatives of coumarin were also used in 2 additional trials (9, 15). Adjusted-Dose Warfarin Compared with Placebo In six trials involving 2900 patients with a total of 186 strokes, anticoagulation with oral vitamin K antagonists was compared with placebo (in five trials [1, 3, 7-9]) or control (in one trial [6]) (Table 2). The mean age of participants at study entry was 69 years (approximately 20% of participants were>75 years of age). Twenty-nine percent of participants were women, 45% had hypertension, and 20% had previous stroke or TIA. The target range for the international normalized ratio (INR) varied (Table 2); the mean achieved INR ranged from 2.0 to 2.6 in the five primary prevention trials and was 2.9 in the single secondary prevention trial. Mean duration of follow-up ranged from 1.2 to 2.3 years (overall average, 1.6 years per participant). The rate of stroke among participants who were not assigned to receive anticoagulation averaged 4.6% per year for primary prevention and 12.3% per year for secondary prevention. Four of these six trials were stopped at an interim analysis because of treatment efficacy (1, 3, 6, 8). Table 2. Adjusted-Dose Warfarin Compared with Placebo Meta-analysis showed that therapy with adjusted-dose warfarin reduced the relative risk for stroke by 62% (95% CI, 48% to 72%). This effect was statistically significant in four individual trials (3, 6, 8, 9) (Figure). The pooled result of primary prevention trials (59% reduction) was similar to that from the secondary prevention trial (68% reduction); results from the two double-blind trials (58% reduction) (7, 8) and the four open-label trials (63% reduction) (1, 3, 6, 9) were also similar. Warfarin was associated with similar relative risk reductions in disabling stroke (59%) and nondisabling stroke (61%). The absolute risk reduction for all stroke was 2.7% per year (number needed to treat [NNT] for 1 year to prevent one stroke, 37) for primary prevention and 8.4% per year (NNT, 12) for secondary prevention. Figure. Effects on all stroke (ischemic and hemorrhagic) of therapies for patients with atrial fibrillation. Top. Middle. Bottom. When only ischemic strokes were considered, treatment with adjusted-dose warfarin was associated with a 65% (CI, 52% to 74%) relative risk reduction. Twice as many intracranial hemorrhages were identified in participants who were assigned to receive warfarin (six compared with three), but the difference was not statistically significant. The rate of intracranial hemorrhage averaged 0.3% per year during anticoagulation and was 0.1% per year with placebo. The rate of major extracranial hemorrhage averaged 0.6% per year in patients who received placebo. The relative risk for major extracranial hemorrhage was 2.4 (CI, 1.2 to 4.6; absolute risk increase, 0.3% per year) for participants who received warfarin (excluding one trial in which almost half of the control group took aspirin [6]). All-cause mortality decreased in participants who received warfarin (relative risk reduction, 26% [CI, 4% to 43%]; P>0.2 for homogeneity; absolute risk reduction, 1.6% per year). Antiplatelet Therapy Compared with Placebo Six trials compared antiplatelet therapy with placebo (1, 3, 9, 13, 14, 16). In these trials, 3337 participants experienced a total of 376 strokes while being randomly assigned to receive antiplatelet therapy or placebo (Table 3). In five trials (1, 3, 9, 14, 16), assignment was double-blind. Approximately 90% of total follow-up exposure during antiplatelet therapy was with aspirin alone. Aspirin dosage ranged from 25 mg twice daily to 1300 mg/d. On the basis of available data from the three largest trials (1, 3, 9), the mean age of participants was 70 years (about 33% of participants were>age 75 years). Thirty-eight percent of participants were women, 46% had hypertension, and 40% had previous stroke or TIA. Mean duration of follow-up in these trials ranged from 1.2 to 4 years (overall average, 1.5 years per participant). The average rate of stroke among participants assigned to placebo was 5.2% per year for primary prevention and 12.9% per year for secondary prevention. Table 3. Antiplatelet Agents Compared with Placebo Meta-

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration

Summary Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.

The aim of this new statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches for the implementation of guidelines and their use in high-risk populations.

Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.

BACKGROUND Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial

BACKGROUND Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. METHODS In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. FINDINGS 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. INTERPRETATION Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial. FUNDING National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).

Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage

Objective: To characterize the rates of recurrent intracranial hemorrhage (ICH), ischemic stroke, and death in survivors of primary ICH. Methods: Systematic review of studies reporting recurrent stroke in survivors of primary ICH, identified at index ICH and followed forward. Studies were identified by computerized search of the literature and review of reference lists. Results: Ten studies published between 1982 and 2000 reporting 1,880 survivors of ICH, followed for a total of 6,326 patient-years (mean follow-up, 3.4 patient-years), were included. The aggregate rate of all stroke from five studies was 4.3% per patient-year (95% CI, 3.5% to 5.4%). The rate in the three population-based studies was higher than in the two hospital-based studies, 6.2% versus 4.0% per patient-year (p = 0.04). About three fourths of recurrent strokes were ICH. Considering all 10 studies, a total of 147 patients had a recurrent ICH, an aggregate rate of 2.3% per patient-year (95% CI, 1.9% to 2.7%). Based on data from four studies, patients with a primary lobar ICH had a higher rate of recurrent ICH than those with a deep, hemispheric ICH (4.4% versus 2.1% per patient-year; p = 0.002). The aggregate rates of subsequent ischemic stroke and mortality were 1.1% per patient-year (95% CI, 0.8% to 1.7%) and 8.8% per patient-year (95% CI, 5.2% to 11.0%). Conclusions: Recurrent stroke among survivors of primary ICH occurs at a rate of about 4% per patient-year, and most are recurrent ICH. Survivors of ICH have a higher risk of recurrent ICH than of ischemic stroke, and this has implications for the use of antithrombotic agents in these patients.

Cerebral microbleeds: Histopathological correlation of neuroimaging

Background: In recent years, there has been a growing interest in cerebral microbleeds (CMBs) and their role in cerebrovascular disease. A few studies have investigated the histopathological correlation between CMBs and neuroimaging findings. We conducted a systematic review in an attempt to characterize the pathological and radiological correlation. Methods: A systematic literature search was conducted for studies in which CMBs were characterized histopathologically and correlated with MRI findings. Results: Five studies met the inclusion criteria, with a total of 18 patients. Hemosiderin deposition was reported in 42 CMBs (49%), while 16 CMBs (19%) were described as old hematomas which stained for iron, 13 (15%) had no associated specific pathology, 11 (13%) contained intact erythrocytes, 1 (1%) was due to vascular pseudocalcification, 1 (1%) was a microaneurysm and 1 (1%) was a distended dissected vessel. Lipofibrohyalinosis was the most prominent associated vascular finding. Amyloid angiopathy was present primarily in patients with dementia. Conclusions: Although histopathological associations have been observed using MRI in patients with CMBs, the findings have yet to be validated and further research is warranted.

Increased Risk of Intracranial Hemorrhage when Aspirin Is Combined with Warfarin: A Meta-Analysis and Hypothesis

Background: Oral anticoagulation with vitamin K antagonists increases the risk of intracranial hemorrhage; whether addition of aspirin to oral anticoagulation augments this risk is unclear. Methods: Meta-analysis of randomized clinical trials in which aspirin was added to oral anticoagulants. Results: Six randomized clinical trials were identified, including a total of 3,874 participants. Use of aspirin with oral anticoagulants was associated with more than double the frequency of intracranial hemorrhage (relative risk = 2.4, 95% CI = 1.2–4.8, p = 0.02). Conclusion: We hypothesize that aspirin when added to oral vitamin K antagonists may increase the risk of intracranial hemorrhage, but this observation requires confirmation. The magnitude of this effect is uncertain, and the clinical importance is likely different for different patient populations.

The Secondary Prevention of Small Subcortical Strokes (SPS3) study.

Background Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. Methods Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n=3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy – 325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind – and to one of two levels of systolic blood pressure targets –‘intensive’ (<130 mmHg) vs. ‘usual’ (130–149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment. Conclusions Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.

Prognostic Importance of Leukoaraiosis in Patients With Symptomatic Internal Carotid Artery Stenosis

Background and Purpose— Leukoaraiosis (LA) is a frequent finding on brain CT scans. This study examined patients with LA and symptomatic internal carotid artery disease. Methods— Patients in the North American Symptomatic Carotid Endarterectomy Trial were evaluated for the extent of LA. Long-term prognosis and perioperative risk associated with carotid endarterectomy were assessed. Results— Among 2618 patients, 493 had LA: 354 restricted and 139 widespread. Patients with LA were older, had a history of hypertension, had more hemispheric ischemic events (particularly stroke), and had small, deep brain infarcts. The 3-year risks of stroke for medically treated patients were 20.2% (no LA), 27.3% (restricted LA), and 37.2% (widespread LA) (P =0.01). For surgically treated patients, the risks were 14.2%, 25.4%, and 33.6%, respectively (P <0.001). With widespread LA, occurrence of disabling strokes doubled in medical patients and tripled in surgical patients. The 30-day perioperative risks of any stroke or death for surgical patients with 50% to 99% internal carotid artery stenosis were 5.3% (no LA), 10.6% (restricted LA), and 13.9% (widespread LA). Despite higher perioperative risk, endarterectomy reduced the absolute 3-year risk of stroke ipsilateral to the symptomatic 50% to 99% stenosed artery by 11.6% (P =0.46) for patients with widespread LA, 7.6% (P =0.39) with those with restricted LA, and 10.9% (P <0.001) for those with no LA. Conclusions— In patients with a transient ischemic attack or nondisabling stroke associated with internal carotid artery disease, presence of LA was associated with an increased risk of any stroke and of disabling or fatal stroke. Patients with widespread LA had the worst prognosis. Despite the higher perioperative risk, endarterectomy reduced the risk of stroke.