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).

Development and validation of health system performance measures for opioid use disorder in British Columbia, Canada.

BACKGROUND: Performance measurement provides an evidence-based means to inform development of interventions to improve the quality of care for people who use opioids. We aimed to develop and assess the predictive validity of health system performance measures for opioid use disorder (OUD) in British Columbia (BC), Canada. METHODS: Performance measures were generated using retrospective population-level administrative datasets (both provincial and regional) and publicly-reported retrospective data according to four domains (care engagement, clinical guideline compliance, integration, and healthcare utilization). The adjusted odds ratio was estimated via generalized linear mixed models to determine predictive validity for all-cause hospitalization or mortality within 6 months of measurement. FINDINGS: A total of 102 performance measures were constructed. We identified 55,470 diagnosed PWOUD, and 39,456 ever engaged in opioid agonist treatment (OAT). We found divergent rates of treatment for concurrent conditions (7.4% for alcohol use disorder to 80.1% for HIV/AIDS), low levels of linkage to OAT and other outpatient care following acute care, and increasing levels of service provision, including increases in OAT prescribers and pharmacies, naloxone kit distribution and overdose prevention site visitation. Our analyses on the predictive validity measures largely supported a priori hypotheses on the direction of effect on the outcome. CONCLUSIONS: We identified a range of priorities to improve the quality of care for PWOUD, with critical gaps in linkage to care through acute care settings and long-term engagement in OAT. The proposed measures can be derived for geographic and clinical subgroups and updated over time, providing a basis to monitor and evaluate efforts to address the public health burden of OUD.

Determinants of selection into buprenorphine/naloxone among people initiating opioid agonist treatment in British Columbia.

BACKGROUND: Studies assessing the comparative effectiveness of methadone versus buprenorphine/naloxone for opioid use disorder in real-world settings are rare - challenged by structural differences in delivery across settings and factors influencing treatment selection. We identified determinants of selection into buprenorphine/naloxone and quantified contributions of individual and provider-level covariates in a setting delivering both medications within the same healthcare settings. METHODS: Utilizing linked health administrative datasets, we conducted a retrospective cohort study of people with opioid use disorder (PWOUD) receiving opioid agonist treatment (OAT) in British Columbia, Canada, from 2008-2017. Determinants of buprenorphine/naloxone selection were identified using a generalized linear mixed model with random intercept terms for providers and individuals. We determined the influence of individual demographics, clinical history, measures of provider experience and preference, and dates of key policy changes. RESULTS: A total of 39,605 individuals experienced 178,976 OAT episodes (methadone:139,439(77.9 %);buprenorphine/naloxone:39,537(22.1 %)). Male sex, less OAT experience, younger age, mental health conditions and chronic pain were associated with higher odds of buprenorphine/naloxone prescription. For providers, higher client-attachment, more complex OAT case-mixes, and higher buprenorphine/naloxone prescribing-preference were also associated with higher odds of buprenorphine/naloxone prescription. Observed individual-level covariates explained 9.7 % of variance in odds of buprenorphine/naloxone selection, while observed provider-level covariates explained 20.0 %. Controlling for covariates, residual unmeasured between-individual variance accounted for 18.5 % of the explained variation in the odds of buprenorphine/naloxone selection, while unmeasured between-provider variance accounted for 28.4 %. CONCLUSION: Provider characteristics were more influential in selection of buprenorphine/naloxone over methadone informing subsequent analyses of comparative effectiveness of these regimens.

Histamine and spermidine content in brain during development.

Histamine concentration in fetal rat brain is high at 17 days gestation but decreases sharply just before birth. Values subsequently increase to a maximum postnatal concentration 5 to 10 days after birth, and then steadily decline to low adult values by time of weaning. Spermidine follows a pattern similar to that of histamine but with a 24- to 48-hour lag. The developmental pattern for histamine in the central nervous system is different from that for other neural amines. It appears that the marked fetal and neonatal changes in brain histamine correlate best with periods of rapid cell proliferation and growth during brain maturation.

Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks.

BACKGROUND: Non-valvular atrial fibrillation (AF) carries an increased risk of stroke mediated by embolism of stasis-precipitated thrombi originating in the left atrial appendage. Both oral anticoagulants and antiplatelet agents have proven effective for stroke prevention in most patients at high risk for vascular events, but primary stroke prevention in patients with non-valvular AF potentially merits separate consideration because of the suspected cardio-embolic mechanism of most strokes in AF patients. OBJECTIVES: To characterize the relative effect of long-term oral anticoagulant treatment compared with antiplatelet therapy on major vascular events in patients with non-valvular AF and no history of stroke or transient ischemic attack (TIA). SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (June 2006). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to June 2006) and EMBASE (1980 to June 2006). We contacted the Atrial Fibrillation Collaboration and experts working in the field to identify unpublished and ongoing trials. SELECTION CRITERIA: All unconfounded, randomized trials in which long-term (more than four weeks) adjusted-dose oral anticoagulant treatment was compared with antiplatelet therapy in patients with chronic non-valvular AF. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed quality and extracted data. The Peto method was used for combining odds ratios after assessing for heterogeneity. MAIN RESULTS: Eight randomized trials, including 9598 patients, tested adjusted-dose warfarin versus aspirin (in dosages ranging from 75 to 325 mg/day) in AF patients without prior stroke or TIA. The mean overall follow up was 1.9 years/participant. Oral anticoagulants were associated with lower risk of all stroke (odds ratio (OR) 0.68, 95% confidence interval (CI) 0.54 to 0.85), ischemic stroke (OR 0.53, 95% CI 0.41 to 0.68) and systemic emboli (OR 0.48, 95% CI 0.25 to 0.90). All disabling or fatal strokes (OR 0.71, 95% CI 0.59 to 1.04) and myocardial infarction (OR 0.69, 95% CI 0.47 to 1.01) were substantially but not significantly reduced by oral anticoagulants. Vascular death (OR 0.93, 95% CI 0.75 to 1.15) and all cause mortality (OR 0.99, 95% CI 0.83 to 1.18), were similar with these treatments. Intracranial hemorrhages (OR 1.98, 95% CI 1.20 to 3.28) were increased by oral anticoagulant therapy. AUTHORS' CONCLUSIONS: Adjusted-dose warfarin and related oral anticoagulants reduce stroke, disabling stroke and other major vascular events for those with non-valvular AF by about one third when compared with antiplatelet therapy.

Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators.

OBJECTIVES: This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations. BACKGROUND: Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF. METHODS: Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial. RESULTS: TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities < or = 20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF. CONCLUSIONS: TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.

Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators.

OBJECTIVE: This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation (AF). BACKGROUND: Although intermittent AF is common, relatively little is known about the attendant risk of stroke. METHODS: A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years. Independent risk factors for ischemic stroke were identified by multivariate analysis. RESULTS: Patients with intermittent AF were, on average, younger (66 vs. 70 years, p < 0.001), were more often women (37% vs. 26% p < 0.001) and less often had heart failure (11% vs. 21%, p < 0.001) than those with sustained AF. The annualized rate of ischemic stroke was similar for those with intermittent (3.2%) and sustained AF (3.3%). In patients with intermittent AF, independent predictors of ischemic stroke were advancing age (relative risk [RR] = 2.1 per decade, p < 0.001), hypertension (RR = 3.4, p = 0.003) and prior stroke (RR = 4.1, p = 0.01). Of those with intermittent AF predicted to be high risk (24%), the observed stroke rate was 7.8% per year (95% confidence interval 4.5 to 14). CONCLUSIONS: In this large cohort of AF patients given aspirin, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation. High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF.

Epidemiologic features of asymptomatic cerebral infarction in patients with nonvalvular atrial fibrillation.

We performed unenhanced computed tomographic scans on 141 asymptomatic patients with nonvalvular atrial fibrillation. Thirty-six patients (26%) had hypodense areas consistent with cerebral infarction. The majority of these were small deep infarcts, seen in 29 patients (21%), but 13 patients (9%) had cortical or large deep infarctions. Twelve patients had more than one infarct on computed tomographic scan. Increasing age and increased left atrial diameter were the only clinical features associated with asymptomatic infarction. Patients older than 65 years with a left atrial diameter greater than 5.0 cm (n = 23) had a 52% prevalence of asymptomatic infarction. Patients younger than 65 years with a left atrial diameter less than 5.0 cm (n = 38) had an 11% prevalence of silent infarction. Patients with only one of these risk factors (n = 72) had a 24% prevalence of silent infarction. Infarction was more common in those with chronic (34%) as opposed to intermittent (22%) nonvalvular atrial fibrillation, but this difference was not significant. Hypertension, diabetes, duration of atrial fibrillation, congestive heart failure, history of myocardial infarction, and echocardiographic evidence of left ventricular dysfunction were not associated with asymptomatic infarction. A history of hypertension was present in only 35% of our patients with small-deep asymptomatic infarction, similar to the percentage in patients without stroke. Asymptomatic cerebral infarction is common in nonvalvular atrial fibrillation. The association with enlarged left atria and the lack of correlation with major cerebrovascular risk factors suggests a cardioembolic mechanism. Further study is needed to determine the functional and prognostic significance of these strokes.

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.

Design and expression of a stable bispecific scFv dimer with affinity for both glycophorin and N9 neuraminidase.

We have designed and produced a stable bispecific scFv dimer (bisFv) by non-covalent association of two hybrid VH-VL pairs derived from an anti-neuraminidase antibody (NC10) and an anti-glycophorin antibody (1C3). The bisFv dimer was demonstrated to have binding activity to the two respective target antigens and was evaluated as a reagent for rapid whole blood agglutination assays. The bisFv was expressed in the periplasm of Escherichia coli, from a secretion vector which comprised two cistrons in tandem under the control of a single lac promoter, inducible with IPTG. Each cistron encoded one of the hybrid VH-VL pairs, with V domains separated by a linker region encoding the five amino acids, Gly4Ser. The short linker region was designed to prevent association of VH and VL regions of the same molecule and favour the formation of dimers. The protein synthesized from each hybrid scFv cistron was directed to the E. coli periplasm by the inclusion of distinctive signal secretion sequences preceding each hybrid gene; from pel B of Erwinia cartovora and from gene III of fd phage. The bisFv was affinity-purified from culture supernatants via the C-terminal tag epitope FLAG and was shown, by FPLC on a Superose 6 column, to be consistent in size with that of a scFv dimer. The bisFv was stable for more than 4 months at 4 degrees C and was shown by BIAcore analysis to bind to either target antigen, human glycophorin, or tern N9 neuraminidase. Simultaneous binding to both target antigens was demonstrated when a pre-formed bisFv-neuraminidase complex was shown to bind to immobilized glycophorin. In whole blood agglutination assays, the bisFv dimer was able to agglutinate red blood cells when crosslinked with an anti-idiotype antibody (3-2G12) binding to the NC10 combining site, but no agglutination occurred on binding the antigen neuraminidase. These results are a function of the topology of the epitopes on neuraminidase and have implications for the use of relatively rigid bifunctional molecules (as bisFv dimers) to cross link two large membrane-anchored moieties, in this case, red blood cell glycophorin and neuraminidase, an M(r) 190,000 tetramer.

Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis.

BACKGROUND AND PURPOSE: The goal of this study was to examine the hypotheses that retinal ischemia is caused more often by carotid atherosclerosis than by atrial fibrillation and that the odds of retinal events compared with hemispheric events increase with worsening carotid stenosis. METHODS: We used data from the Stroke Prevention in Atrial Fibrillation (SPAF) I through III trials and North American Symptomatic Carotid Endarterectomy Trial (NASCET), calculating hemispheric:retinal (H:R) odds for the territory of ischemic events during follow-up in patients with atrial fibrillation and medically treated 50% to 99% carotid stenosis or occlusion in the respective trials. RESULTS: The H:R odds were 25:1 in the SPAF aspirin-assigned patients and 2:1 for NASCET vessels. In NASCET patients, the H:R odds of recurrent ischemic events were 1:4 for vessels randomized initially for retinal symptoms compared with 6:1 for those randomized for hemispheric events (significant difference; P<0.001). Moreover, the H:R odds of first events in the territory of the contralateral asymptomatic artery were 1:1 if the randomized vessel had retinal symptoms compared with 4:1 if the randomized vessel had hemispheric symptoms (significant difference; P<0.01). Increasing carotid stenosis in the 50% to 99% range had no effect on H:R odds (P=0.8). CONCLUSIONS: These findings confirm that retinal symptoms are more typical of carotid stenosis. Hemodynamic effects do not appear to be more important in the pathogenesis of retinal events than hemispheric ones in carotid stenosis. The retinal versus hemispheric location of initial symptoms is strongly predictive of the location of subsequent events in patients with carotid stenosis, even when new symptoms are contralateral to the original ones.

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.

Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

The Stroke Prevention in Atrial Fibrillation II study compared the efficacy and safety of aspirin and warfarin in patients with atrial fibrillation. Three neurologists, blinded to patient therapy, categorized the pathophysiology of ischemic strokes that occurred in the trial based on predetermined clinical criteria. Upon analyzing the patients being treated with these two drugs, warfarin proved significantly more effective than aspirin in preventing cardioembolic strokes (p = 0.005) and strokes of uncertain pathophysiology (p = 0.01). There was no significant difference in the efficacy for prevention of noncardioembolic strokes.

Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism. Stroke Prevention in Atrial Fibrillation Investigators.

Ischemic strokes occurring in patients with nonrheumatic atrial fibrillation are due to a variety of mechanisms, not exclusively to cardiogenic embolism. Without knowledge of antithrombotic therapy assignment, we categorized strokes in the Stroke Prevention in Atrial Fibrillation Study as presumed cardioembolic or noncardioembolic. We then compared patient clinical and echocardiographic variables, as well as the efficacy of aspirin prophylaxis, for each stroke type. Of 71 ischemic strokes, we categorized 46 (65%) as cardioembolic, 13 (18%) as noncardioembolic, and 12 (17%) as of uncertain cause. Patients developing noncardioembolic strokes, relative to cardioembolic strokes, were more commonly men (p = 0.005) and were more likely to have left ventricular wall motion abnormalities by two-dimensional echocardiography (p = 0.002). Aspirin reduced the occurrence of strokes categorized as noncardioembolic significantly more than it did those categorized as cardioembolic (p = 0.01). These results emphasize the value of considering stroke mechanisms in therapeutic trials of antithrombotic agents and suggest a differential effect of aspirin according to mechanism.

Assessment of three schemes for stratifying stroke risk in patients with nonvalvular atrial fibrillation.

PURPOSE: The risk of ischemic stroke varies widely among patients with nonvalvular atrial fibrillation, influencing the choice of prophylactic antithrombotic therapy. We assessed three schemes for stroke risk stratification in these patients who were treated with aspirin and who did not have prior cerebral ischemia. SUBJECTS AND METHODS: Criteria from three schemes of risk stratification were applied to a longitudinally observed cohort of patients with atrial fibrillation who did not have prior cerebral ischemia and who were treated with aspirin alone or aspirin combined with low, ineffective doses of warfarin in a multicenter clinical trial. The ability of the schemes to identify patients at high (>/=6%), low (75 years old as high risk (observed stroke rate 4.2 per 100 person-years), while the remaining scheme classified one third of patients in this age group as low risk (observed stroke rate 0.6 per 100 person-years). CONCLUSIONS: When tested in a large cohort of patients with atrial fibrillation who were treated with aspirin, available risk-stratification schemes successfully identified patients with low rates of ischemic stroke, but less consistently identified high-risk patients.

Plasmin-alpha2-antiplasmin complex in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

Plasmin-alpha2-antiplasmin complex (PAP) is an index of recent fibrinolytic activity. We examined PAP levels in patients with atrial fibrillation (AF) to determine whether these levels are correlated with clinical characteristics associated with stroke risk. We obtained blood for measurement of PAP in a non-random sample of 586 patients with AF on entering the Stroke Prevention in Atrial Fibrillation III Study. PAP levels were measured with an ELISA assay. PAP values were transformed with a natural logarithm (PAPln) prior to all analyses. Older age, female gender, recent congestive heart failure, decreasing fractional shortening, recent onset of AF, and coronary artery disease were each univariately associated with higher levels of PAP (all p<0.05, two-sample t-test, simple linear regression). Older age, recent congestive heart failure, decreasing fractional shortening, and recent onset of AF were independently associated with higher PAP levels by multivariate analysis (linear regression). Among patients receiving warfarin, PAP levels were not correlated with INR levels (linear regression, p=0.60). Patients classified as high-risk for thromboembolism by our risk stratification criteria (systolic blood pressure > 160 mm Hg, prior thromboembolism, recent congestive heart failure, poor left ventricular function, and women over age 75) had higher PAP levels than low-risk patients (antilog mean PAPln 5.6 vs 4.9. p<0.001, two-sample t-test). PAP levels in patients with AF are associated with clinical characteristics predictive of thromboembolism. Elevated PAP levels are particularly associated with poor left ventricular function and are not affected by anticoagulation. PAP levels may be a marker of stroke risk in patients with AF.

Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. SPAF TEE Investigators. Stroke Prevention and Atrial Fibrillation. Transesophageal echocardiography.

Patients with atrial fibrillation and with documented aortic plaque who were assigned to adjusted-dose warfarin therapy (international normalized ratio 2.0 to 3.0) had an annual rate of cholesterol embolization of 0.7% (95% confidence interval [CI] 0.1% to 5.3%/patient-year). Warfarin-assigned patients with plaque had a lower rate of embolic events (5.9%/year; 95% CI 3.0 to 12) than those on combination low-dose warfarin (international normalized ratio <1.5) plus aspirin (17.3%/year; 95% CI 11 to 27; p = 0.01).

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

Stroke associated with atrial fibrillation (AF) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (LAA). Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography (TEE) in patients with AF have not been defined. To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient features, TEE findings, and subsequent cardioembolic events were correlated with velocity by multivariate analysis. Patients in AF during TEE displayed lower peak antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20 cm/s was associated with dense spontaneous echocardiographic contrast (P <.001), appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01). Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF and associated with spontaneous echocardiographic contrast, appendage thrombus, and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis, independent clinical predictors of stroke in patients with AF, also correlated with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the generation of stasis, thrombus formation, and embolism in patients with AF, although other mechanisms also contribute to stroke.

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: II. Dense spontaneous echocardiographic contrast (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

We analyzed transesophageal echocardiograms from 772 participants in the Stroke Prevention in Atrial Fibrillation (SPAF-III) study, characterizing spontaneous echocardiographic contrast (SEC) in the left atrium or appendage as faint or dense. The association of dense SEC with stroke risk factors and anatomic, hemodynamic, and hemostatic parameters related to specific thromboembolic mechanisms was evaluated by multivariate analysis. Spontaneous echocardiographic contrast was present in 55% of patients and was dense in 13%. Age (odds ratio [OR] 2.4/decade, P <.001), constant atrial fibrillation (OR 6.9, P <.001), history of hypertension (OR 3. 2, P <.001), and current tobacco smoking (OR 2.6, P =.04) were independent clinical predictors of dense SEC. Multivariate analysis of clinical, echocardiographic, and hemostatic parameters yielded age as the sole independent clinical predictor of dense SEC (OR 2. 4/decade, P <.001). Other independent predictors were measures of left atrial/appendage flow dynamics, left atrial size (OR 2.4/cm diameter, M-mode, P <.001), atherosclerotic aortic plaque (OR 2.8, P =.002), and plasma fibrinogen >350 mg/dL (P <.001). Results were similar when SEC of any density was analyzed. In conclusion, SEC occurred in more than half of these patients with prospectively defined nonvalvular atrial fibrillation but was usually faint. Dense SEC was strongly associated with previously reported clinical predictors of stroke, linking them to thromboembolism through atrial stasis. Diverse pathophysiologic factors including atrial stasis, fibrinogen level, and aortic plaque influence SEC.

Growth factor profiles in breast cyst fluid identify women with increased breast cancer risk.

Gross cystic disease and breast cancer are hormonally induced diseases that may share a common biochemical environment conducive to abnormal proliferative responses. Breast cyst fluid samples were analyzed for specific growth factors and levels were compared with breast cancer risk. Growth factor profiles identified both women at increased breast cancer risk and subgroups of women with distinct clinical manifestations of gross cystic disease. Women at increased risk for breast cancer demonstrated in their breast cyst fluid lower levels of platelet-derived growth factor and transforming growth factor (TGF)-beta, compared to women at lower risk. The presence of multiple cysts was associated with increased mitogenic activity, increased epidermal growth factor (EGF) and TGF-beta breast cyst fluid levels, and recurrent cysts were associated with higher levels of EGF. Unique growth factor profiles were associated with each risk group or clinical state, suggesting that distinct proliferative environments, associated with different clinical outcomes, are present in the breast tissue of women with gross cystic disease.