Cathy M. Helgason

Development of aspirin resistance in persons with previous ischemic stroke.

The ex vivo effect of aspirin (ASA) on platelet aggregation, the platelet component of thrombosis, was studied at repeated intervals in a cohort of patients taking aspirin for recurrent ischemic stroke prevention to define the maintenance of efficacy over time. Methods We administered increasing doses of aspirin (from 325 to 1300 mg/d) to patients with previous ischemic stroke and determined the extent of inhibition of platelet aggregation after 2 weeks and thereafter at approximately 6-month intervals. Results Over 33 months, 306 patients had platelet aggregation studies performed to define their initial response to ASA therapy. Of these, 228 had complete and 78 had partial inhibition of platelet aggregation at initial testing. To date, 119 of those who had complete inhibition and 52 who had partial inhibition have undergone repeat testing at least once. At repeat testing 39 of the 119 (32.7%) with complete inhibition at initial testing had lost part of the antiplatelet effect of ASA and converted from complete to partial inhibition without change in ASA dosage. Of the 52 with partial inhibition at initial testing, 35 achieved complete inhibition either by ASA dosage escalation (in 325 mg/d increments) or fluctuation of response at the same dosage, but 8 of those 35 (22.8%) had reverted to partial inhibition when tested again. Overall, 8.2% of patients ultimately exhibited ASA resistance to 1300 mg/d-8 of 52 (15.4%) with partial inhibition and 6 of 119 (5.0%) with complete inhibition at initial testing. Conclusions The antiplatelet (and presumably the antithrombotic) effect of a fixed dose of ASA is not constant over time in all individuals. The mechanisms by which increased dosage requirement or ASA resistance develops and the clinical significance of this development are currently undefined.

American Heart Association Prevention Conference IV: Prevention and Rehabilitation of Stroke Introduction

The fourth American Heart Association Prevention Conference was held May 1-2, 1996, in Tucson, Ariz. This report of the conference presents the state of knowledge on stroke epidemiology, etiologic basis, treatment, and rehabilitation. Since the conference, enthusiasm for and activity in acute stroke treatment has increased, spurred by the encouraging and successful National Institutes of Health trial of tissue plasminogen activator (TPA). This document attests to the large variety of conditions that contribute to stroke. The challenge for the future will be to forge a better understanding of the interaction of pathogenic risk factors, causes, and physiology. Evidence-based medicine should provide a scientific framework that can be used in the prevention and treatment of stroke in individual patients. The untimely death of Dr Mike Pessin, who chaired the Acute Interventions panel, has deeply saddened all of us. His presence and contributions will be sorely missed. We thank the section chairs and panel members who contributed many hours and their expertise to the preparation of this paper. We are indebted to the American Heart Association, which contributes to the dominant and driving force in stroke research and treatment. Mark L. Dyken, MD The best treatment for stroke is prevention. If stroke cannot be prevented, the next best treatment is to prevent permanent deficit. AHA Prevention ConferenceIV is dedicated to the prevention and rehabilitation of stroke, with an emphasis on risk factors, etiology, acute intervention, and rehabilitation. Leaders in the field will define where we are and where we need to go. To put this in perspective, the evolution of properly designed studies, the recognition of risk factors, and the evidence that risk factors can be altered must be reviewed. No matter how sophisticated the design and statistical techniques, all studies must have the same fundamentals: There must be a testable hypothesis, …

Aspirin response and failure in cerebral infarction

Background and Purpose The purpose of this study was to assess the biological effect of aspirin as measured by the inhibition of platelet aggregation in patients taking aspirin for stroke prevention and in patients with acute stroke. Methods We administered increasing doses of aspirin (325,650,975, and 1,300 mg daily) to 113 patients for stroke prevention and measured the inhibition of platelet aggregation in these patients and in 33 patients with acute stroke taking aspirin before stroke onset. Results Eighty-five patients on ≤325 and six on ≥650 mg aspirin daily had complete inhibition of platelet aggregation. Increase of the dose by 325 mg in nine of the 22 patients with partial inhibition of platelet aggregation produced complete inhibition in five patients at 650 mg and in one at 975 mg. At 1,300 mg, three patients still had only partial inhibition of platelet aggregation (aspirin resistance). Of the 33 inpatients with acute stroke, 24 had platelet aggregation studies done before further administration of aspirin. Of these, 19 had complete inhibition of platelet aggregation and three had partial inhibition, with production of complete inhibition of platelet aggregation at dose escalation; one patient was aspirin-resistant and the other noncompliant. Conclusions How the inhibition of platelet aggregation relates to stroke prevention remains unclear. The ability of aspirin and the dose required to inhibit platelet aggregation may depend upon the individual.

Carotid Stenosis in Patients With Atrial Fibrillation: Prevalence, Risk Factors, and Relationship to Stroke in the Stroke Prevention in Atrial Fibrillation Study

BACKGROUND Several mechanisms contribute to the increased stroke rate of patients with atrial fibrillation (AF). We assessed the frequency of carotid artery stenosis in patients with AF and its relationship to stroke during aspirin or warfarin therapy. METHODS Carotid ultrasonography was done in 676 patients with AF enrolled in the Stroke Prevention in Atrial Fibrillation Study to detect cervical carotid stenosis of 50% or more of the luminal diameter. The presence of carotid stenosis was correlated with patient features and subsequent stroke during a mean of 2.6 years of follow-up. RESULTS In patients with AF who were older than 70 years, the frequency of carotid stenosis was 12% in men and 11% in women. Carotid stenosis was independently associated with systolic hypertension (relative risk, 2.4; P = .002), diabetes (relative risk, 1.8; P = .04), and tobacco use (relative risk, 1.8; P = .02). Carotid stenosis did not add significantly to prediction of stroke when analyzed with other clinical risk factors for stroke in patients with AF (relative risk, 1.3; 95% confidence interval, 0.5 to 3.6; P = .55). CONCLUSIONS Carotid artery stenosis of 50% or more occurs in about 12% of elderly patients with AF, reflecting the substantial prevalence of hypertension and diabetes in these patients. Carotid stenosis was not usefully predictive of stroke in patients with AF who were given aspirin or warfarin. Routine ultrasonography to detect carotid stenosis does not appear warranted in patients with AF without previous symptoms of brain ischemia.

Etiology of Stroke

The diagnosis of arterial stroke differentiates ischemia from hemorrhage. The former may be due to arterial occlusion or stenosis, the latter to leakage or rupture of an artery. Computed tomography (CT) and magnetic resonance imaging (MRI) have shown that this basic differentiation cannot be reliably made from the history and clinical examination alone. Of the clinical stroke syndromes, only Wallenberg’s syndrome has not been reported to be due to hemorrhage. When CT or MRI is not available for diagnosis, spinal tap is reliably positive only when the aneurysm or arteriovenous malformation has ruptured into the subarachnoid space; the results are often normal when a small hemorrhage occurs in the parenchyma. For some therapies, notably neuroprotective agents, the potential benefits for ischemia do not seem to be offset by potential harm in the case of hemorrhage. However, because fibrinolytics, antithrombotic agents, or surgery are treatment options, diagnostic certainty is essential to avoid harming the patient. Most—but not all—strokes have a sudden or rapidly evolving onset. Differential diagnosis of sudden change in focal neurological status includes seizures or postepileptic paralysis, hemorrhage into a tumor (itself a form of stroke), and migraine. Neuroimaging helps to differentiate between these and the cause of short-lived symptoms (transient ischemic attack [TIA]) usually presumed due to ischemia but possibly due to new-onset infarction or hemorrhage. More precise classification of stroke into a pathogenic subtype (embolism, thrombosis, decreased perfusion or “lacunar” infarction, leakage, or rupture) evades the best clinical skills. The classification of stroke mechanism depends on the presence of risk factors for stroke (preexisting condition or circumstance epidemiologically related to stroke) and etiologies (disease directly causing the mechanism) that implicate the cause of stroke in a given patient. However, more than one risk factor and etiology are frequently present in the same patient and may be related …

Factors influencing warfarin dose requirements in African–Americans

INTRODUCTION African-Americans are under-represented in studies assessing contributors to warfarin response. Our primary objective was to determine whether the genes for cytochrome P450 (CYP) 2C9, nicotinamide adenine dinucleotide phosphate, reduced, quinone oxidoreductase (NQO1) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are associated with warfarin dose requirements in African-Americans. PATIENTS AND METHODS The following factors were assessed: demographics; clinical data; the CYP2C9 Arg144Cys (*2), Ile358Leu (*3) and Asp360Glu (*5); NQO1 Pro187Ser (*1/*2); and VKORC1 G6853C genotypes were analyzed in 115 African-Americans on stable warfarin doses. RESULTS Allele frequencies were 0.05 for the CYP2C9 *2, *3 or *5 alleles; 0.20 for NQO1 *2; and 0.25 for VKORC1 6853C. Possession of a CYP2C9*2, *3 or *5 allele was associated with a 38% lower warfarin dose compared with the *1/*1 genotype (30 +/- 13 vs 48 +/- 18 mg/week; p = 0.003). Neither the NQO1 *1/*2 nor VKORC1 G6853C genotype was associated with warfarin dose requirements in the population as a whole or in CYP2C9*1 allele homozygotes. Multiple regression analysis revealed that CYP2C9 genotype (p = 0.015), age (p < 0.001) and body surface area (p < 0.001) were jointly associated with warfarin dose requirements, and together explained 33% of the variability in warfarin dose requirements among African-Americans. DISCUSSION Our data suggest that CYP2C9 genotype, age and body size are important determinants of warfarin dose requirements in African-Americans. Our data further suggest that the VKORC1 G6853C polymorphism alone may not be useful for predicting warfarin dose requirements in this racial group.

The fuzzy cube and causal efficacy: representation of concomitant mechanisms in stroke

Twentieth century medical science has embraced nineteenth century Boolean probability theory based upon two-valued Aristotelian logic. With the later addition of bit-based, von Neumann structured computational architectures, an epistemology based on randomness has led to a bivalent epidemiological methodology that dominates medical decision making. In contrast, fuzzy logic, based on twentieth century multi-valued logic, and computational structures that are content addressed and adaptively modified, has advanced a new scientific paradigm for the twenty-first century. Diseases such as stroke involve multiple concomitant causal factors that are difficult to represent using conventional statistical methods. We tested which paradigm best represented this complex multi-causal clinical phenomenon-stroke. We show that the fuzzy logic paradigm better represented clinical complexity in cerebrovascular disease than current probability theory based methodology. We believe this finding is generalizable to all of clinical science since multiple concomitant causal factors are involved in nearly all known pathological processes.

Capsular hypesthetic ataxic hemiparesis.

Twenty-three patients with hypesthetic ataxic hemiparesis underwent computed tomography or magnetic resonance imaging. Twenty-two patients had infarcts of lacunar or slightly larger size in the contralateral posterior limb of the internal capsule. In 15 patients the infarct extended superiorly into the adjacent paraventricular region, and in seven it extended into the lateral thalmus. In eight patients the infarct was limited to the posterior limb of the internal capsule, and in only two patients was an ipsilateral to capsular pontine lacune found. Despite a location similar to that of pure motor and pure sensory lacunar stroke, hypesthetic ataxic hemiparesis correlates with larger infarcts, most often located in the posterior medial superior territory of the anterior choroidal artery. Some infarcts appeared to be localized immediately posterolateral to this region, in the posterior cerebral artery territory. The presence and extent of infarction is better detected by the addition of magnetic resonance imaging to computed tomography.

Platelet aggregation in patients with atrial fibrillation taking aspirin or warfarin.

Background and Purpose Although warfarin and perhaps aspirin may be effective in preventing thromboembolism in patients with nonvalvular atrial fibrillation, some patients develop cerebral infarction despite these therapies. The purpose of this study was to determine inhibition of platelet aggregation in patients on aspirin and platelet reactivity in those on warfarin in the Stroke Prevention in Atrial Fibrillation study. Methods Twenty-four patients in the Stroke Prevention in Atrial Fibrillation study at the University of Illinois at Chicago, 17 on enteric-coated aspirin 325 mg/d and 7 on warfarin to produce an International Normalized Ratio of 2.0 to 4.5, had platelet aggregation studies performed during a 10-month period and interpreted by an investigator blinded to therapy. Epinephrine, adenosine diphosphate, collagen, and arachidonic acid were used as aggregating agents. Compliance was determined by pill count for those patients on aspirin. Results Seven patients taking aspirin had partial and 10 had complete inhibition of platelet aggregation. Three of seven patients on warfarin had hyperaggregable platelets. Compliance was 80% or greater for those patients taking aspirin. One patient on warfarin had partial inhibition of platelet aggregation. Conclusions Some patients in the Stroke Prevention in Atrial Fibrillation trial on aspirin 325 mg/d did not achieve complete inhibition of platelet aggregation. Others had hyperaggregable platelets. These findings suggest platelet-dependent mechanisms for aspirin and warfarin failure to prevent stroke in these patients.

Design of a multicenter randomized trial for the stroke prevention in atrial fibrillation study

Individuals with nonvalvular atrial fibrillation are at increased risk of stroke. The Stroke Prevention in Atrial Fibrillation Study is a 15-center randomized clinical trial examining the risks and benefits of low-intensity warfarin (prothrombin time of 1.3-1.8 times control) and aspirin (325 mg/day) in patients with constant or intermittent atrial fibrillation. Candidates for anticoagulation (group I) are randomized to receive warfarin in an open-label fashion, aspirin, or placebo; the last two treatments are given in a double-blind fashion. Warfarin-ineligible patients (group II) are randomized to receive aspirin or placebo in a double-blind fashion. Primary end points are ischemic stroke and systemic embolism. Secondary end points are death, transient ischemic attack, myocardial infarction, and unstable angina pectoris. Analysis is based on the intention-to-treat principle. The anticipated rate of primary end points in patients receiving placebo is 6%/yr. The sample size of 1,644 patients is based on a projected reduction in the rate of primary end points of 50% by warfarin and of 33% by aspirin (beta = 0.2, alpha = 0.05). Patient entry commenced in June 1987 and will continue for 3 years, with an additional year of follow-up. High-risk subsamples identified by clinical and echocardiographic criteria are sought prospectively.