J. P. Mohr

Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis

BACKGROUND Carotid-artery stenting and carotid endarterectomy are both options for treating carotid-artery stenosis, an important cause of stroke. METHODS We randomly assigned patients with symptomatic or asymptomatic carotid stenosis to undergo carotid-artery stenting or carotid endarterectomy. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization. RESULTS For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P=0.84) or sex (P=0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P=0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P=0.01), and for myocardial infarction (1.1% vs. 2.3%, P=0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85). CONCLUSIONS Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)

Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study.

Background—Patent foramen ovale (PFO) is associated with stroke, but there are no randomized studies to evaluate the efficacy of antithrombotic therapies. Methods and Results—The PFO in Cryptogenic Stroke Study was a 42-center study that evaluated transesophageal echocardiographic findings in patients randomly assigned to warfarin or aspirin in the Warfarin-Aspirin Recurrent Stroke Study. In this study, 630 stroke patients were enrolled, of whom 312 (49.5%) were randomized to warfarin and 318 (50.5%) to aspirin. Of these, 265 patients experienced cryptogenic stroke and 365 experienced known stroke subtypes. End points were recurrent ischemic stroke or death. PFO was present in 203 patients (33.8%). There was no significant difference in the time to primary end points between those with and those without PFO in the overall population (P =0.84; hazard ratio 0.96; 95% CI 0.62 to 1.48; 2-year event rates 14.8% versus 15.4%) or in the cryptogenic subset (P =0.65; hazard ratio 1.17; 95% CI 0.60 to 2.37; 2-year event rates 14.3% versus 12.7%). There was no significant difference among those with no, small, or large PFO (P =0.41 for small PFO and P =0.16 for large PFO; 2-year event rates for no, small, and large PFO, 15.4%, 18.5%, and 9.5%, respectively). There was no significant difference between patients with isolated PFO and those with PFO in association with atrial septal aneurysm (P =0.84; 2-year event rates 14.5% versus 15.9%). In patients with PFO, there was no significant difference in the time to primary end points between those treated with warfarin and those treated with aspirin (P =0.49; hazard ratio 1.29; 95% CI 0.63 to 2.64; 2-year event rates 16.5% versus 13.2%). Conclusions—On medical therapy, the presence of PFO in stroke patients did not increase the chance of adverse events regardless of PFO size or the presence of atrial septal aneurysm.

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

BACKGROUND The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. METHODS Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. FINDINGS Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. INTERPRETATION The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. FUNDING National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Morning increase in onset of ischemic stroke.

The time of onset of ischemic stroke was determined for 1,167 of 1,273 patients during the collection of data by four academic hospital centers between June 30, 1983, and June 30, 1986. More strokes occurred in awake patients from 10:00 AM to noon than during any other 2-hour interval. The incidence of stroke onset declined steadily during the remainder of the day and early evening. The onset of stroke is least likely to occur in the late evening, before midnight.

Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation

BACKGROUND A small proportion of strokes are caused by cerebral arteriovenous malformations (AVM). Treatment to prevent intracranial haemorrhage itself carries risks, and untreated AVM may in many cases have a good prognosis. We investigated the risk of subsequent symptomatic bleeding in the clinical course of AVM in patients with and without an initial haemorrhage. METHODS 281 unselected, consecutive, prospectively enrolled patients with cerebral AVM were grouped according to their initial clinical presentation--142 presented with and 139 without haemorrhage. The frequency of AVM haemorrhages during the subsequent clinical course (before the start of endovascular, surgical, or radiation treatment) in the two groups was compared by means of Kaplan-Meier life-tables, log-rank test, and multivariate proportional-hazards regression models. Haemorrhage was defined as a clinically symptomatic event with signs of acute bleeding on computed tomography or magnetic resonance brain imaging. FINDINGS During mean follow-up of 8.5 months for the haemorrhage group and 11.9 months for the non-haemorrhage group, haemorrhages occurred in 18 (13%) of the former patients and in three (2%) of the latter (p=0.0002). The annual risk of haemorrhage was 17.8% and 2.2%, respectively. In the multivariate regression model, the adjusted hazard ratio for haemorrhage at initial presentation was 13.9 (95% CI 2.6-73.8; p=0.002). Deep venous drainage (hazard ratio 4.1 [1.2-14.9], p=0.029) and male sex (9.2 [2.1-41.3], p=0.004) were also significantly associated with subsequent haemorrhage, but no significant association was found for age or AVM size. The annual rate of spontaneous haemorrhage was 32.6% for men and 10.4% for women in the haemorrhage group compared with 3.3% for men and 1.3% for women in the non-haemorrhage group. Among patients with haemorrhage at initial presentation, the risk of haemorrhage fell from 32.9% in year 1 to 11.3% in subsequent years (34.2% to 31.0% in men; 31.1% to 5.5% in women). INTERPRETATION In AVM, patients initially presenting with haemorrhage have a higher risk of subsequent bleeding than those presenting with other symptoms. The risk is higher in men than in women.

Dementia after stroke Baseline frequency, risks, and clinical features in a hospitalized cohort

We determined the frequency of dementia in a cohort of 251 patients aged ⩾60 years hospitalized with acute ischemie stroke, based on examinations performed 3 months after stroke onset. Using modified DSM-III-R criteria, we found dementia in 66 patients (26.3%). Diagnostic agreement among raters was excellent (kappa = 0.96). In a control sample of 249 stroke-free subjects recruited from the community and matched by age, we found dementia in eight subjects (3.2%). Using a logistic regression model to estimate the risk of dementia associated with stroke in the combined samples, the odds ratio (OR) for stroke patients compared with control subjects was 9.4 (p <0.001). Advancing age and fewer years of education were significant, independent correlates of dementia, with a trend evident for race (non-white versus white). Confining the analysis to subjects residing in the Washington Heights-Inwood community of northern Manhattan, the OR was 10.3 (p <0.001) with significant age and race effects. We conclude that ischemie stroke significantly increases the risk of dementia, with independent contributions by age, education, and race.

The pilot Stroke Data Bank: definition, design, and data.

Four university centers collaborated to contribute 1158 patients with acute episodes of cerebrovascular disease to the pilot Stroke Data Bank, initiated by NINCDS in 1978. During the pilot project a standard set of data collection forms were developed and used at each of the collaborating centers. Data on clinical course, laboratory findings, therapy and outcome were gathered prospectivcly throughout the patients hospitalization and at specified follow-up intervals. Using operational definitions of stroke sub-types, consecutive cases were systematically allocated to specific categories of brain and vascular pathology. The definitions were based on clinical criteria as well as on laboratory data, including computer- ized tomography (CT), and angiography findings. This paper describes the pilot Stroke Data Bank and presents the distribution of cases by diagnostic and demographic categories. It represents one of the largest series of prospectively collected stroke cases studied by CT (90% of the cases) and angiography (42%). Based upon the methods and processes of this pilot study, a main phase of the Stroke Data Bank has been established to address a number of questions pertaining to stroke classification, evolution, diagnosis, and prognosis. Stroke Vol 15, No 4, 1984

Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study.

Background and Purpose Patent foramen ovale is associated with ischemic stroke in patients without a clearly identifiable etiology for stroke (cryptogenic stroke). Paradoxical embolization is thought to be a potential mechanism. How- ever, patent foramen ovale is also found in patients with known cause of stroke. Therefore, using contrast transesophageal echocardiography, we characterized the patent foramen ovale in cryptogenic stroke patients to assess morphological factors that may contribute to paradoxical embolization. Methods Contrast transesophageal echocardiographic studies of 74 consecutive patients referred for ischemic stroke were reviewed. Twenty-three patients with patent foramen ovale were identified. These patients were classified as having strokes of determined origin or cryptogenic strokes according to criteria developed for the Stroke Data Bank of the National Institute of Neurological Disorders and Stroke. Separation of septum primum from secundum and the number of microbubbles appearing in left atrium were then quantitated. These parameters were compared between patients with cryptogenic stroke and those with known cause of stroke. Results The patent foramen ovale dimension was significantly larger in patients with cryptogenic stroke compared with patients with an identifiable cause of stroke (2.1 ±1.7 mm versus 0.57±0.78 mm [mean±SD]; P<.01). The number of microbubbles was also greater in patients with cryptogenic stroke compared with patients with an identifiable cause of stroke (13.9±10.7 versus 1.6±0.8 [mean±SD]; P<.0O05). Conclusions Patients with cryptogenic stroke have larger patent foramen ovale with more extensive right-to-left interatrial shunting than patients with stroke of determined cause. Transesophageal echocardiographically identifiable characteristics of patent foramen ovale may be important in defining the clinical significance of individual patent foramina.

Comparison of diagnostic techniques for the detection of a patent foramen ovale in stroke patients.

Background and Purpose The prevalence of a patent foramen ovale has been shown to be increased in patients with ischemic stroke. Transesophageal echocardiography, transthoracic echocardiography, and transcranial Doppler examination with contrast injection can all be used to search for a patent foramen ovale. We compared the accuracy of these techniques for identifying a patent foramen ovale in 49 patients with acute ischemic stroke or transient ischemic attack. Methods Transcranial Doppler examination of the right middle cerebral artery was performed during simultaneous transthoracic echocardiography with aerated saline injection, and again during transesophageal echocardiography; the latter was adopted as the “gold standard” for assessing the sensitivity of the other two tests. Results Contrast transesophageal echocardiography detected a patent foramen ovale in 19 of 49 patients (39%), during normal respiration in 15 of them and during Valsalva maneuver in 4. Transcranial Doppler correctly identified 13 patients with a patent foramen ovale and all 30 patients without it. Therefore, the sensitivity of transcranial Doppler was 68% (13/19), and its specificity 100% (30/30). The 6 patients misclassified by transcranial Doppler (false negatives) had a very small right-to-left shunt detected by transesophageal echocardiography. Contrast transthoracic echocardiography was found to be the least sensitive test, detecting a patent foramen ovale in only 9 of 19 patients (47%). The specificity of transthoracic echocardiography was 100% (30/30 patients). The low sensitivity of transthoracic echocardiography was principally due to the suboptimal image quality obtained in false-negative patients. Both transcranial Doppler and transthoracic echocardiography were more sensitive in patients with cryptogenic stroke than in patients with stroke of determined origin. This may indicate the presence of larger, more easily detectable shunts in patients with cryptogenic stroke. Conclusions Transesophageal echocardiography is more sensitive than transcranial Doppler examination in detecting a patent foramen ovale, but only in cases of minimal right-to-left shunts, the clinical relevance of which remains to be established. The sensitivity of transthoracic echocardiography is heavily hampered by the frequency of inadequate heart visualization.

Determinants of early recurrence of cerebral infarction. The Stroke Data Bank.

We studied 1,273 patients with ischemic cerebral infarction who were entered into the Stroke Data Bank, a prospective, observational study involving four university hospitals and the Biometry and Field Studies Branch of the National Institute of Neurological Disorders and Stroke. Forty patients had noniatrogenic recurrent stroke within 30 days after the index cerebral infarction. Using life tables, the 30-day cumulative +/- SE risk of early recurrence for all infarctions was 3.3 +/- 0.4%. The risk of early recurrence was greatest for atherothrombotic infarction (7.9 +/- 2.2%, eight of 113 patients) and least for lacunar infarction (2.2 +/- 1.2%, eight of 337 patients). Both cardioembolic infarction (4.3 +/- 0.9%, 10 of 246 patients) and infarction of undetermined cause (3.0 +/- 0.5%, 14 of 508 patients) had intermediate risks. History of hypertension and diabetes mellitus, as well as diastolic hypertension and elevated blood sugar concentration at admission, were associated with early recurrence. Logistic regression analysis estimated the risk of early recurrence to be 8.56% in those with coexisting hypertension and a glucose concentration of 300 mg/dl versus 0.77% in the absence of these two abnormalities. Early recurrence was associated with longer median duration of initial hospital stay (27 vs. 14 days) and a higher 30-day case-fatality rate (20% vs. 7.4%). Increased weakness scores were associated with early recurrent stroke. Identification of the determinants of early recurrent stroke may lead to better secondary prevention and may help select high-risk patients for further study.