Worse blood pressure control in patients with cerebrovascular or peripheral arterial disease compared with coronary artery disease.

OBJECTIVES: Poor blood pressure (BP) control is common amongst patients with symptomatic atherothrombotic disease. It is unclear whether BP control and management differ across atherothrombotic disease subtypes. METHODS: We analysed the baseline data of 44,984 patients with documented coronary artery disease (CAD) only (n = 30,414), cerebrovascular disease (CVD) only (n = 11,359) and peripheral arterial disease (PAD) only (n = 3211) from the international REduction of Atherothrombosis for Continued Health Registry and investigated the impact of atherothrombotic disease subtype on BP control and use of antihypertensive drugs. RESULTS: The proportion of patients with BP controlled (<140/90 mmHg) was higher in CAD (58.1%) than in CVD (44.8%) or PAD (38.9%) patients (P < 0.001). Amongst patients with treated hypertension, CAD patients were more likely to have BP controlled than were CVD patients [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.59-1.75] or PAD (OR = 2.30; 95% CI = 2.10-2.52). These differences were smaller in women than in men and decreased with age. Amongst treated patients, CAD patients were more likely to receive > or =3-drug combination therapies than were CVD (OR = 1.73; 95% CI = 1.64-1.83) or PAD (OR = 1.64; 95% CI = 1.49-1.80) patients. Adjustment for age, gender, waist obesity, diabetes, education level and world region did not alter the results. CONCLUSIONS: Coronary artery disease patients are more likely than CVD or PAD patients to have BP controlled and to receive antihypertensive drugs, particularly combination therapies. Promotion of more effective BP control through combination antihypertensive therapies could improve secondary prevention and therefore prevent complications in CVD and PAD patients.

High cardiovascular event rates in patients with asymptomatic carotid stenosis: the REACH Registry.

BACKGROUND AND PURPOSE: Data on current cardiovascular event rates in patients with asymptomatic carotid artery stenosis (ACAS) are sparse. We compared the 1-year outcomes of patients with ACAS > or =70% versus patients without ACAS in an international, prospective cohort of outpatients with or at risk of atherothrombosis. METHODS: The Reduction of Atherothrombosis for Continued Health Registry enrolled patients with either > or =3 atherothrombotic risk factors or established atherothrombotic disease. We investigated the 1-year follow-up data of patients for whom physicians reported presence/absence of ACAS at the time of inclusion. RESULTS: Compared with patients without ACAS (n = 30 329), patients with ACAS (n = 3164) had higher age- and sex-adjusted 1-year rates of transient ischaemic attack (3.51% vs. 1.61%, P < 0.0001), non-fatal stroke (2.65% vs. 1.75%, P = 0.0009), fatal stroke (0.49% vs. 0.26%, P = 0.04), cardiovascular death (2.29% vs. 1.52%, P = 0.002), the composite end-point cardiovascular death/myocardial infarction/stroke (6.03% vs. 4.29%, P < 0.0001) and bleeding events (1.41% vs. 0.81%, P = 0.002). In patients with ACAS, Cox regression analyses identified history of cerebrovascular ischaemic events as most important predictor of future stroke (HR 3.21, 95% CI 1.82-5.65, P < 0.0001). CONCLUSION: Asymptomatic carotid artery stenosis was associated with high 1-year rates of cardiovascular and cerebrovascular ischaemic events. Stroke was powerfully predicted by prior cerebrovascular ischaemic events.

Current strategies for ischemic stroke prevention: role of multimodal combination therapies.

Stroke remains a global leading cause of death and long-term disability, highlighting the need for more effective treatment approaches. The majority of strokes are of ischemic origin, often caused by large- or small-artery atherothrombosis, or cardioembolism. Considering the systemic nature of the atherothrombotic disease process, stroke patients are at increased risk for ischemic events in several vascular territories: cerebral, coronary and peripheral. Due to the limited options for acute stroke therapies, stroke prevention is an important therapeutic approach. In addition to the management of modifiable risk factors such as hypertension, dyslipidemia and smoking through pharmacotherapy or lifestyle adjustments, anticoagulants, surgical and perhaps endovascular approaches are indicated in certain patients. Antiplatelet therapies using various agents are a cornerstone of secondary stroke prevention. To ensure the appropriate continuum of care after hospitalization for ischemic stroke, some interventions for the prevention of recurrent ischemic stroke should be initiated during the acute hospitalization setting and maintained in the out-patient setting.

Acute physiological derangement is associated with early radiographic cerebral infarction after subarachnoid haemorrhage.

BACKGROUND: Cerebral infarction after aneurysmal subarachnoid haemorrhage (SAH) is presumed to be due to cerebral vasospasm, defined as arterial lumen narrowing from days 3 to 14. METHODS: We reviewed the computed tomography scans of 103 patients with aneurysmal SAH for radiographic cerebral infarction and controlled for other predictors of outcome. A blinded neuroradiologist reviewed the angiograms. Cerebral infarction from vasospasm was judged to be unlikely if it was visible on computed tomography within 2 calendar days of SAH or if angiography showed no vasospasm in a referable vessel, or both. RESULTS: Cerebral infarction occurred in 29 (28%) of 103 patients with SAH. 18 patients had cerebral infarction that was unlikely to be due to vasospasm because it was visible on computed tomography by day 2 (6 (33%)) or because angiography showed no vasospasm in a referable artery (7 (39%)), or both (5 (28%)). In a multivariate model, cerebral infarction was significantly related to World Federation of Neurologic Surgeons grade (odds ratio (OR) 1.5/grade, 95% confidence interval (CI) 1.1 to 2.01, p = 0.006) and SAH-Physiologic Derangement Score (PDS) >2 (OR 3.7, 95% CI 1.4 to 9.8, p = 0.01) on admission. Global cerebral oedema (OR 4.3, 95% CI 1.5 to 12.5, p = 0.007) predicted cerebral infarction. Patients with cerebral infarction detectable by day 2 had a higher SAH-PDS than patients with later cerebral infarction (p = 0.025). CONCLUSIONS: Many cerebral infarctions after SAH are unlikely to be caused by vasospasm because they occur too soon after SAH or because angiography shows no vasospasm in a referable artery, or both. Physiological derangement and cerebral oedema may be worthwhile targets for intervention to decrease the occurrence and clinical impact of cerebral infarction after SAH.

Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina. Receptor suppression using integrilin therapy (PURSUIT) trial. The PURSUIT Investigators.

BACKGROUND: The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates. METHODS AND RESULTS: We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke. CONCLUSIONS: Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.

A multicenter study of anticoagulation parameters when using heparin and warfarin.

Anticoagulation with heparin and warfarin is used in the treatment of several diseases including cerebrovascular disease. While the most effective therapeutic range of anticoagulation is unclear, some investigators have found an increased risk of bleeding complications with more intense anticoagulation. Recent studies have suggested that lower levels of anticoagulation may be as efficacious as high levels but with a reduced incidence of bleeding complications. In order to better assess the anticoagulation parameters used by neurologists and house officers, we performed a questionnaire survey at six major medical centers. Responses were obtained from 30 attending neurologists and 52 house officers. Attending physicians and house officers selected mean partial thromboplastin times of 57.7 s and 63.3 s, respectively. The mean prothrombin time (PT) was 21.0 s for attending neurologists and 19.4 s for house officers. The average PT ratio was 1.82 for attending neurologists and 1.69 for house officers. Forty percent of attending neurologists and 17.7% of house officers specified PT ratios of 2.0 or greater. These results indicate that many physicians may be using warfarin in dosages above recommended guidelines.

A molecular genetic study of intracerebral hemorrhage.

BACKGROUND: Two forms of inherited intracerebral hemorrhage (ICH) are associated with an amyloid angiopathy caused by mutations in the genes for the amyloid precursor protein or cystatin C. The purpose of this study was to determine whether patients with sporadic ICH have mutations in the amyloid precursor protein or cystatin C genes. METHODS: Consecutive patients with ICH admitted to the neurology or neurosurgery services at Duke University Hospital, Durham, NC, were studied. Using the polymerase chain reaction, we amplified exons 16 and 17 of the amyloid precursor protein and exon 2 of cystatin C and sequenced the products. Twenty-six men and 22 women were studied. The ICH location was deep in 29 patients, lobar in 16, cerebellar in two, and brain stem in one. There were 30 patients (63%) with a positive family history of stroke; seven of them (15%) had a family history of ICH. CONCLUSIONS: Mutations previously reported to cause familial forms of ICH were not found in this group of patients.

Dysphagia following brain-stem stroke. Clinical correlates and outcome.

We studied 23 individuals (16 men, seven women; mean age 57 years) who had brainstem strokes confirmed by computed tomography of the head or magnetic resonance imaging. Videofluoroscopic modified barium-swallowing examination showed aspiration in 15 of 23 patients. Of the 15 aspirating patients, the majority had bilateral strokes with multiple lesion loci, most often in association with large-vessel disease. All 15 patients had involvement of the pons or medulla. Statistical analyses revealed a significant association between aspiration and pharyngeal residue observed under videofluoroscopy, cranial nerve IX abnormality, vocal fold weakness, and severe dysarthria. Despite initial severity, recovery was good. Following an aggressive program of aspiration prevention, over 80% of patients resumed full oral nutrition at the last follow-up.

tPA in acute ischemic stroke: United States experience and issues for the future.

The approval of tissue plasminogen activator (tPA) for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of an acute stroke. Despite this approval and the lack of an alternative therapy, the use of tPA in stroke has been quite low. Several explanations for this underutilization have been identified, including lack of patient awareness, potential complications, infrastructure deficiencies, and physician concerns. This article explores these issues and suggests strategies for improving the use of tPA as an acute therapy in stroke.

Suppression of recurrent transient ischemic attacks by a statin agent.

Recent studies of hydroxy-methylglutaryl coenzyme A reductase inhibitors have demonstrated that therapy with statins is associated with a significant decrease in the risk of stroke and TIA in patients with coronary artery disease. The underlying mechanism responsible for this effect is unclear. The author presents two patients who had cessation of TIAs upon institution of statin therapy. A variety of non-lipid-lowering mechanisms may account for this beneficial effect. This initial observation, if confirmed by further study, may suggest a role for statin agents in preventing recurrent TIAs.

APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis.

OBJECTIVE: To determine whether a specific apolipoprotein E (APOE) polymorphism is a risk factor for ischemic cerebrovascular disease (CVD; stroke or TIA). BACKGROUND: The APOE epsilon4 allele is overrepresented in AD, atherosclerosis, and ischemic heart disease. In addition, epsilon4 carriers have higher plasma cholesterol levels than non-epsilon4 carriers. METHODS: Using Medline (OVID and PubMed), a search was performed for all studies that examined APOE in ischemic CVD. The authors identified nine case-control studies that were suitable for analysis. RESULTS: There were 926 patients with ischemic stroke or TIAs and 890 age- and sex-matched control subjects. Overall analysis revealed a significantly higher APOE-epsilon4 allelic frequency in affected patients compared with control subjects (0.14 versus 0.09; odds ratio, 1.68; 95% CI, 1.36 to 2.09; p<0.001). There was a significant excess of the epsilon3 allele (0.85 versus 0.80) but not the epsilon2 allele (0.06 versus 0.06) in the control subjects compared with the ischemic CVD patients. Seven studies had data on APOE genotypes. Carriers of epsilon4 were more frequent among ischemic CVD patients than control subjects (27% versus 18%; odds ratio, 1.73; 95% CI, 1.34 to 2.23; p<0.001). CONCLUSIONS: The APOE-epsilon4 allele and carriers of epsilon4 are more frequent among patients with ischemic CVD compared with control subjects. The epsilon2 allele does not appear to be protective for ischemic CVD. These findings imply a role for the APOE genotype in the pathogenesis of some cases of ischemic CVD.

A follow-up survey of clinical practices for the use of heparin, warfarin, and aspirin.

OBJECTIVE: To determine whether anticoagulation practices have changed when heparin and warfarin are used to treat cerebrovascular disease, and to determine the dosage of aspirin used to treat carotid territory transient ischemic attacks (TIAs). BACKGROUND: A 1987 study documented that neurologists and neurology house officers were using excessive amounts of heparin and warfarin. Recent studies have demonstrated the efficacy and safety of low-intensity anticoagulation for preventing strokes, but no data are available on how these findings have affected the treatment practices of clinicians. DESIGN/METHODS: Questionnaires were sent to neurology staff at 10 medical centers. The questions dealt with the use of heparin, warfarin, and aspirin in stroke/transient ischemic attack patients. The nonparametric Wilcoxon rank sum test was used for analyzing the responses. RESULTS: Ninety-three physicians responded compared with 52 in the prior study. Most (56 of 92; 61%) did not use an IV heparin bolus. The mean partial thromboplastin time (PTT) was 55 seconds, which was significantly less than the mean PTT of 62 seconds (p = 0.006) in the prior study. The mean prothrombin time (PT) fell to 16.0 seconds (range, 12.5 to 20.0) compared with a mean of 19.9 seconds (range, 15.0 to 27.0; p < 0.001) in the earlier study. There was a significant fall in the mean PT ratio from 1.74 (range, 1.20 to 2.25) to 1.49 (range, 1.12 to 2.50; p < 0.001). Most respondents used 325 mg qd of aspirin for treating TIAs. CONCLUSIONS: At the centers studied, neurologists and neurology house officers are using less intense anticoagulation when treating stroke patients now than in 1986. This concurs with recent studies demonstrating the efficacy and safety of low-intensity anticoagulation in some clinical settings. The use of 325 mg/d of aspirin is common, although the data supporting its efficacy compared with higher doses are unclear.

Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes.

We investigated whether early hematoma or edema volumes could explain the adverse association between APOE epsilon4 and survival in intracerebral hemorrhage. Among 102 patients, epsilon4 carriers had a higher mortality rate than non-epsilon4 carriers (38 versus 24%, p = 0.05). Nonsurvivors had larger hematoma (75.5 cm3 versus 27.1 cm3, p<0.001) and edema volumes (37.5 cm3 versus 17.1 cm3, p<0.01), but these were not associated with epsilon4 after adjusting for race, age, and type of hemorrhage.

Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

Advances in the genetics of cerebrovascular disease and stroke.

MEDLINE searches identified epidemiologic, experimental, and clinical studies on the genetics of cerebrovascular disease and stroke, including the following topics: genetic epidemiology of stroke; genetics of systemic disorders that cause ischemic stroke, including coagulation disorders, connective tissue disorders, vasculopathies, metabolic disorders, and disorders of unknown etiology; and genetics of systemic disorders that cause hemorrhagic stroke. Recent discoveries in stroke genetics involve the genetic basis of monogenic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and sickle cell disease. Reproducing similar advances in other forms of cerebrovascular disease and stroke will be more difficult because their inheritance is complex, multigenic, and heterogeneous. However, the future is promising with the application of molecular genetic approaches such as linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses as well as the transmission/disequilibrium test--a statistical method for detection of linkage between a marker and a disease-susceptibility locus.

Diagnosis and treatment of ischemic stroke.

Most patients who have a stroke are evaluated initially by a primary care physician. For patients to benefit from new stroke therapies that must be initiated within a few hours of stroke onset, primary care physicians must be prepared to diagnose stroke and initiate acute treatment. This article provides information on the rapid and accurate diagnosis and management of patients with acute ischemic stroke. This information is particularly relevant due to the relatively high risk:benefit ratio associated with some acute stroke therapies, such as tissue plasminogen activator. Information is also provided about medical and surgical therapies to prevent subsequent strokes.

Hyperacute stroke therapy with tissue plasminogen activator.

The past year has seen tremendous progress in developing new therapies aimed at reversing the effects of acute stroke. Thrombolytic therapy with various agents has been extensively studied in stroke patients for the past 7 years. Tissue plasminogen activator (t-PA) received formal US Food and Drug Administration approval in June 1996 for use in patients within 3 hours of onset of an ischemic stroke. Treatment with t-PA improves neurologic outcome and functional disability to such a degree that, for every 100 stroke patients treated with t-PA, an additional 11-13 will be normal or nearly normal 3 months after their stroke. The downside of t-PA therapy is a 6% rate of symptomatic intracerebral hemorrhage (ICH) and a 3% rate of fatal ICH. Studies are under way to determine whether t-PA can be administered with an acceptable margin of safety within 5 hours of stroke, to evaluate the therapeutic benefits of intraarterial pro-urokinase, and to assess the use of magnetic resonance spectroscopy to identify which patients are most likely to benefit from thrombolysis. Combination thrombolytic-neuroprotectant therapy is also being studied. In theory, patients could be given an initial dose of a neuroprotectant by paramedics and receive thrombolytic therapy in the hospital. We are now entering an era of proactive, not reactive, stroke therapies. These treatments may reverse some or all acute stroke symptoms and improve functional outcomes.

Acute hemodynamic changes during carotid artery stenting.

To determine the clinical significance of acute hemodynamic disturbances during stenting in the carotid sinus region, we assessed the relation between intraprocedural changes in heart rate (HR) and blood pressure (BP) and adverse neurologic and cardiac outcomes. Eighteen patients underwent carotid stenting with the Wallstent (Schneider Inc). Suitable candidates had at least 60% diameter stenosis of the carotid artery by angiography. Initial and nadir HR and BP were recorded during the predilatation, stent delivery, and postdilatation periods. Bradycardia was defined as HR < or =60 beats/min and hypotension as systolic BP < or =100 mm Hg. Nineteen Wallstents were successfully deployed in all 19 carotid arteries. Some degree of bradycardia or hypotension occurred in 68% of carotid stent procedures, but administration of vasoactive medications was necessary in only 7 patients (37%) with more persistent hemodynamic disturbances. Hypotension or the need for continuous vasopressor therapy was significantly more common during postdilatation (32%) than in the predilatation period (5%) (p = 0.02). Bradycardia was not reduced by prophylactic atropine. In 1 patient the hemodynamic response to stenting may have contributed to an adverse neurologic and cardiac outcome. Thus, despite frequent fluctuations in HR and BP, most carotid stenting procedures were performed with excellent overall results, even in patients at high risk.

Use of exponential diffusion imaging to determine the age of ischemic infarcts.

OBJECTIVE: Diffusion-weighted magnetic resonance imaging (DWI) detects acute ischemic infarcts with high lesion conspicuity. Determination of infarct age is difficult on DWI alone because infarct signal intensity (SIinfarct) on DWI is influenced by T2 properties ("T2 shine-through"). Maps of the apparent diffusion coefficient (ADC) reflect pure diffusion characteristics without T2 effects but have low lesion conspicuity. Thus, in clinical practice, combined use of DWI and ADC maps is required. Exponential DWI (eDWI) is an innovative means of MRI-diffusion data analysis that merges the advantages of DWI and ADC maps. The authors hypothesized that SIinfarct on eDWI would correlate with infarct age. The authors studied 114 consecutive patients who had 120 ischemic strokes with clearly determined onset times and who underwent echo-planar DWI. The eDWI were generated by dividing the signal intensity on DWI by that on the corresponding T2 image on a pixel-by-pixel basis. SIinfarct on eDWI was measured in the lesion core and expressed as a percentage of contralateral control tissue. On eDWI, relative SIinfarct changed significantly with infarct age (P < .0001). When patients were sorted in infarct-age groups, no significant differences were found within the first 120 hours. However, for patients studied within 5 days, the mean relative SIinfarct was significantly higher compared with patients studied > or = 8 days after stroke (P < .05). For all infarcts up to 5 days old, the eDWI signal intensity was higher than control tissue (hyperintense appearance). All infarcts > 10 days old had an eDWI signal intensity lower than control tissue (hypointense appearance). The authors concluded that the use of eDWI, as a single set of images, reliably differentiates acute infarcts (< or = 5 days old) from infarcts > 10 days old. This feature would be expected to be helpful when the distinction between acute and nonacute infarction cannot be determined on clinical grounds.

Myotonic muscular dystrophy.

Myotonic muscular dystrophy is inherited as an autosomal dominant disease and affects many different organ systems. Genetic research has located the DM gene to chromosome 19. Using new DNA probes, highly accurate genetic counseling can be provided for families with DM. Isolation of the DM gene is expected in the near future and may allow planning of effective therapies.