RESUMEN
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.
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Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides , Analgésicos Opioides/uso terapéutico , Colombia Británica/epidemiología , Humanos , Metadona/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/terapia , Estudios RetrospectivosRESUMEN
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.
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Trastornos Relacionados con Opioides/psicología , Aceptación de la Atención de Salud/psicología , Adulto , Factores de Edad , Colombia Británica , Combinación Buprenorfina y Naloxona/uso terapéutico , Femenino , Humanos , Masculino , Metadona/uso terapéutico , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Factores Sexuales , Adulto JovenRESUMEN
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).
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Antihipertensivos/uso terapéutico , Hipertensión/prevención & control , Accidente Vascular Cerebral Lacunar/prevención & control , Presión Sanguínea/efectos de los fármacos , Hemorragia Cerebral/prevención & control , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Prevención Secundaria , Accidente Vascular Cerebral Lacunar/fisiopatología , Sístole , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
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.
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Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/prevención & control , Administración Oral , Anticoagulantes/administración & dosificación , Hemorragia/etiología , Humanos , Ataque Isquémico Transitorio/prevención & control , Infarto del Miocardio/etiología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/etiologíaRESUMEN
OBJECTIVE: To examine further the relations of plasma von Willebrand factor (vWf, an index of endothelial damage and dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation) concentrations to the presence and onset of clinical congestive heart failure (CHF) and the degree of left ventricular (LV) dysfunction in patients taking part in the SPAF (stroke prevention in atrial fibrillation) study. METHODS: Plasma concentrations of vWf and sP-sel were measured by enzyme linked immunosorbent assay (ELISA) in 1321 participants in the SPAF III study and related to the presence and onset of clinical CHF, as well as echocardiographic findings. Of the 1321 patients with atrial fibrillation (AF), 331 (25%) had a documented history of clinical heart failure, of which 168 cases were related to a new or recurrent episode of acute decompensated heart failure occurring within the preceding three months. RESULTS: Mean plasma vWf was higher among patients with AF and CHF (154 (29) v 144 (31) IU/dl, p < 0.001), particularly those with acute or recent decompensated symptoms. Patients with severe LV dysfunction on two dimensional echocardiography and low fractional shortening also had significantly higher vWf concentrations than those with no LV dysfunction. CHF patients with clinical features--with (156 (28) IU/dl) and without (152 (31) IU/dl) LV dysfunction--also had higher mean vWf concentrations than patients with asymptomatic LV dysfunction (146 (31) IU/dl, p < 0.001). The presence of mitral regurgitation in CHF was associated with lower vWf concentrations. Plasma sP-sel concentrations were not affected by presence, onset, or severity of heart failure. CONCLUSIONS: CHF may contribute to hypercoagulability and thrombotic risk in AF through increased endothelial damage and dysfunction. Patients with acute or recent decompensated features have the highest degree of endothelial damage and dysfunction. The presence of CHF clinical features was an important determinant of plasma vWf concentrations.
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Fibrilación Atrial/sangre , Insuficiencia Cardíaca/sangre , Selectina-P/análisis , Factor de von Willebrand/análisis , Anciano , Anticoagulantes/administración & dosificación , Aspirina/administración & dosificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Inhibidores de Agregación Plaquetaria/administración & dosificación , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/prevención & control , Disfunción Ventricular Izquierda/sangre , Warfarina/administración & dosificaciónRESUMEN
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.
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Fibrilación Atrial/epidemiología , Isquemia Encefálica/epidemiología , Estenosis Carotídea/epidemiología , Enfermedades de la Retina/epidemiología , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Anticoagulantes/uso terapéutico , Fibrilación Atrial/diagnóstico , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/terapia , Comorbilidad , Femenino , Humanos , Ataque Isquémico Transitorio/epidemiología , Masculino , América del Norte/epidemiología , Oportunidad Relativa , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Oclusión de la Arteria Retiniana/epidemiología , UltrasonografíaRESUMEN
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.
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Isquemia Encefálica/epidemiología , Isquemia Encefálica/fisiopatología , Hemorragias Intracraneales/epidemiología , Hemorragias Intracraneales/fisiopatología , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/fisiopatología , Métodos Epidemiológicos , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recurrencia , Factores de TiempoRESUMEN
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.
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Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Fibrilación Atrial/complicaciones , Isquemia Encefálica/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Medición de Riesgo/métodos , Warfarina/uso terapéutico , Adulto , Factores de Edad , Anciano , Isquemia Encefálica/epidemiología , Isquemia Encefálica/etiología , Quimioterapia Combinada , Estudios de Seguimiento , Válvulas Cardíacas , Humanos , Incidencia , Persona de Mediana EdadRESUMEN
Synthetic genes encoding single-chain variable fragments (scFvs) of NC10 anti-neuraminidase antibody were constructed by joining the V(L) and V(H) domains with linkers of fifteen, five, four, three, two, one and zero residues. These V(L)-V(H) constructs were expressed in Escherichia coli and the resulting proteins were characterized and compared with the previously characterized NC10 scFv proteins assembled in V(H)-V(L) orientation. Size-exclusion chromatography and electron microscope images of complexes formed between various NC10 scFvs and anti-idiotype Fab' were used to analyse the oligomeric status of these scFvs. The result showed that as the linker length between V(L) and V(H) was reduced, different patterns of oligomerization were observed compared with those with V(H)-V(L) isomers. As was the case for V(H)-V(L) orientation, the scFv-15 V(L)-V(H) protein existed mainly as a monomer whereas dimer (diabody) was a predominant conformation for the scFv-5, scFv-4 and scFv-3 V(L)-V(H) proteins. In contrast to the V(H)-V(L) isomer, direct ligation of V(L) to V(H) led to the formation of predominantly a tetramer (tetrabody) rather than to an expected trimer (triabody). Furthermore, the transition between dimers and higher order oligomers was not as distinct as for V(H)-V(L). Thus reducing the linker length in V(L)-V(H) from three to two residues did not precisely dictate a transition between dimers and tetramers. Instead, two-residue as well as one-residue linked scFvs formed a mixture of dimers, trimers and tetramers.
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Anticuerpos/inmunología , Región Variable de Inmunoglobulina/química , Neuraminidasa/inmunología , Anticuerpos/química , Cromatografía en Gel , Electroforesis en Gel de Poliacrilamida , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/ultraestructura , Región Variable de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/ultraestructura , Microscopía ElectrónicaRESUMEN
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.
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Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Fibrilación Atrial/complicaciones , Accidente Cerebrovascular/prevención & control , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/etiología , Warfarina/administración & dosificación , Warfarina/efectos adversosRESUMEN
BACKGROUND: While atrial fibrillation (AF) increases the risk of cardioembolic stroke, some ischemic strokes in AF patients are noncardioembolic. OBJECTIVES: To assess ischemic stroke mechanisms in AF and to compare their responses to antithrombotic therapies. METHODS: On-therapy analyses of ischemic strokes occurring in 3,950 participants in the Stroke Prevention in Atrial Fibrillation I-III clinical trials. Strokes were classified by presumed mechanism according to specified neurologic features by neurologists unaware of antithrombotic therapy. RESULTS: Of 217 ischemic strokes, 52% were classified as probably cardioembolic, 24% as noncardioembolic, and 24% as of uncertain cause (i.e., 68% of classifiable infarcts were deemed cardioembolic). Compared to those receiving placebo or no antithrombotic therapy, the proportion of cardioembolic stroke was lower in patients taking adjusted-dose warfarin (p = 0.02), while the proportion of noncardioembolic stroke was lower in those taking aspirin (p = 0.06). Most (56%) ischemic strokes occurring in AF patients taking adjusted-dose warfarin were noncardioembolic vs. 16% of strokes in those taking aspirin. Adjusted-dose warfarin reduced cardioembolic strokes by 83% (p < 0.001) relative to aspirin. Cardioembolic strokes were particularly disabling (p = 0.05). CONCLUSIONS: Most ischemic strokes in AF patients are probably cardioembolic, and these are sharply reduced by adjusted-dose warfarin. Aspirin in AF patients appears to primarily reduce noncardioembolic strokes. AF patients at highest risk for stroke have the highest rates of cardioembolic stroke and have the greatest reduction in stroke by warfarin.
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Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Embolia/complicaciones , Fibrinolíticos/uso terapéutico , Cardiopatías/complicaciones , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Anciano , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Embolia/tratamiento farmacológico , Femenino , Cardiopatías/tratamiento farmacológico , Humanos , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Análisis de Regresión , Factores de Riesgo , Accidente Cerebrovascular/clasificación , Warfarina/administración & dosificación , Warfarina/uso terapéuticoRESUMEN
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.
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Apéndice Atrial/fisiopatología , Fibrilación Atrial/fisiopatología , Embolia y Trombosis Intracraneal/fisiopatología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/fisiopatología , Anciano , Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Apéndice Atrial/diagnóstico por imagen , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico por imagen , Velocidad del Flujo Sanguíneo , Quimioterapia Combinada , Ecocardiografía Doppler de Pulso , Ecocardiografía Transesofágica , Femenino , Frecuencia Cardíaca , Humanos , Embolia y Trombosis Intracraneal/etiología , Masculino , Pronóstico , Factores de Riesgo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Volumen Sistólico , Warfarina/uso terapéuticoRESUMEN
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.
Asunto(s)
Fibrilación Atrial/diagnóstico por imagen , Ecocardiografía Transesofágica/métodos , Embolia y Trombosis Intracraneal/fisiopatología , Accidente Cerebrovascular/prevención & control , Anciano , Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/fisiopatología , Velocidad del Flujo Sanguíneo , Medios de Contraste/administración & dosificación , Quimioterapia Combinada , Ecocardiografía Doppler , Femenino , Humanos , Inyecciones Intravenosas , Embolia y Trombosis Intracraneal/etiología , Embolia y Trombosis Intracraneal/prevención & control , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Factores de Riesgo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/fisiopatología , Warfarina/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation are often elevated in patients with nonvalvular atrial fibrillation, but it is unclear whether such markers usefully predict stroke. Therefore, we undertook the present study to assess the relationship between prothrombin fragment F1.2 (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. The results were correlated with patient features, antithrombotic therapy, and subsequent thromboembolism (ischemic stroke and systemic embolism) by multivariate analysis. RESULTS: Increased F1.2 levels were associated with age (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart failure (P=0.001). F1.2 were not affected by aspirin use and were not associated with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05), and not significantly associated with thromboembolism. Fibrinogen levels were not significantly related to thromboembolism but were associated with elevated BTG levels (P<0.001). The factor V Leiden mutation was not associated with thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated F1.2 levels were associated with clinical risk factors for stroke in atrial fibrillation, whereas increased BTG levels were linked to manifestations of atherosclerosis. In this large cohort of patients with atrial fibrillation who were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not independent, clinically useful predictors of stroke.
Asunto(s)
Fibrilación Atrial/sangre , Factor V/análisis , Fibrinógeno/análisis , Fragmentos de Péptidos/análisis , Protrombina/análisis , Accidente Cerebrovascular/sangre , beta-Tromboglobulina/análisis , Factores de Edad , Anciano , Anticoagulantes/administración & dosificación , Aspirina/administración & dosificación , Biomarcadores/sangre , Femenino , Fibrinolíticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Flebotomía , Factores Sexuales , Tromboembolia/sangre , Warfarina/administración & dosificaciónRESUMEN
PURPOSE: To characterize the efficacy and safety of anticoagulants and antiplatelet agents for prevention of stroke in patients with atrial fibrillation. DATA SOURCES: Randomized trials identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group. STUDY SELECTION: All published randomized trials testing antithrombotic agents to prevent stroke in patients with atrial fibrillation. DATA EXTRACTION: Data on interventions, number of participants, duration of exposure and occurrence of all stroke (ischemic and hemorrhagic), major extracranial bleeding, and death were extracted independently by two investigators. DATA SYNTHESIS: Sixteen trials included a total of 9874 participants (mean follow-up, 1.7 years). Adjusted-dose warfarin (six trials, 2900 participants) reduced stroke by 62% (95% CI, 48% to 72%); absolute risk reductions were 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeding was increased by warfarin therapy (absolute risk increase, 0.3% per year). Aspirin (six trials, 3119 participants) reduced stroke by 22% (CI, 2% to 38%); absolute risk reductions were 1.5% per year for primary prevention and 2.5% per year for secondary prevention. Adjusted-dose warfarin (five trials, 2837 participants) was more efficacious than aspirin (relative risk reduction, 36% [CI, 14% to 52%]). Other randomized comparisons yielded inconclusive results. CONCLUSIONS: Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation, and warfarin is substantially more efficacious than aspirin. The benefit of antithrombotic therapy was not offset by the occurrence of major hemorrhage among participants in randomized trials. Judicious use of antithrombotic therapy, tailored according to the inherent risk for stroke, importantly reduces stroke in patients with atrial fibrillation.
Asunto(s)
Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Fibrilación Atrial/complicaciones , Trastornos Cerebrovasculares/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Warfarina/uso terapéutico , Anticoagulantes/efectos adversos , Aspirina/efectos adversos , Hemorragia/inducido químicamente , Humanos , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto , Warfarina/efectos adversosRESUMEN
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.
Asunto(s)
Antifibrinolíticos , Fibrilación Atrial/sangre , Fibrinolisina/metabolismo , alfa 2-Antiplasmina/metabolismo , Anciano , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Trastornos Cerebrovasculares/etiología , Femenino , Fibrinolisina/análisis , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Warfarina/uso terapéutico , alfa 2-Antiplasmina/análisisRESUMEN
The International Normalized Ratio (INR) system was introduced a decade ago as a way of standardizing the results of prothrombin time testing for patients taking oral anticoagulants. A strong emphasis has been placed upon using thromboplastin reagents that are very sensitive to the effects of oral anticoagulants upon the prothrombin time [i.e. reagents with low International Sensitivity Index (ISI)]. In order to assess how well the INR system functions as currently used in clinical laboratories, we compared the INRs determined using thromboplastins of differing ISIs in samples collected during a large clinical trial of oral anticoagulation for atrial fibrillation (Stroke Prevention in Atrial Fibrillation III trial). Frozen plasma was subjected to prothrombin time testing using thromboplastins with ISIs ranging from 0.97 to 2.49. INRs were calculated using machine-specific ISIs and Westgard's rules were followed to maintain quality control. An unanticipated coagulometer failure allowed a determination of the effect of machine recalibration upon the INR of control plasmas. The correlation between each pair of INRs obtained from 1181 plasmas was high (> 0.9), but the differences between reagents were statistically different from zero (P<0.001 for pairwise comparisons). Plasmas had INRs within the therapeutic range (2.0-3.0) with one reagent but not with another in an average of 20% of instances. Among the 20% discordant pairings, 43% (8.5% of the total tested) showed a difference in INR of more than 0.2 INR units above or below the target range. Low ISI thromboplastins did not perform better in this pairwise comparison than other reagents or the locally determined INR. Recalibration of a coagulometer resulted in a significant change in the INRs obtained from control plasmas (P<0.0001), which confirms and extends the observations of other authors concerning the sensitivity of the INR to coagulometer-related variables. There was a clinically significant difference in the INRs obtained with different thromboplastins, and low ISI reagents did not perform better than others. Since the risk of thrombosis rises sharply below the lower limit of the currently recommended target ranges, consideration should be given to narrowing the recommended range, or advising clinicians to aim for its mid-point. These findings illustrate the difficulties in imposing standardization upon coagulation testing after a test is in widespread use.
Asunto(s)
Fibrilación Atrial/sangre , Relación Normalizada Internacional , Tiempo de Protrombina , Administración Oral , Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Humanos , Indicadores y ReactivosRESUMEN
BACKGROUND: Oral anticoagulation with vitamin K antagonists increases the risk of intracranial hemorrhage; whether addition of aspirin to oral anticoagulation augments this risk is unclear. METHODS: Meta-analysis of randomized clinical trials in which aspirin was added to oral anticoagulants. RESULTS: Six randomized clinical trials were identified, including a total of 3,874 participants. Use of aspirin with oral anticoagulants was associated with more than double the frequency of intracranial hemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p = 0.02). CONCLUSION: We hypothesize that aspirin when added to oral vitamin K antagonists may increase the risk of intracranial hemorrhage, but this observation requires confirmation. The magnitude of this effect is uncertain, and the clinical importance is likely different for different patient populations.
Asunto(s)
Aspirina/efectos adversos , Hemorragia Cerebral/inducido químicamente , Warfarina/efectos adversos , Hemorragia Cerebral/epidemiología , Quimioterapia Combinada , Humanos , Oportunidad Relativa , Medición de RiesgoRESUMEN
BACKGROUND AND PURPOSE: Nonvalvular atrial fibrillation (AF) is a strong, independent risk factor for stroke, but the absolute rate of stroke varies widely among AF patients, importantly influencing the potential benefit of antithrombotic prophylaxis. We explore factors associated with ischemic stroke in AF patients taking aspirin. METHODS: We performed multivariate logistic regression analysis of 2012 participants given aspirin alone or in combination with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I-III trials followed for a mean of 2.0 years, during which 130 ischemic strokes were observed. RESULTS: Age (relative risk [RR]=1.8 per decade, P<0.001), female sex (RR=1.6, P=0.01), history of hypertension (RR=2.0, P<0.001), systolic blood pressure >160 mm Hg (RR=2.3, P<0.001), and prior stroke or transient ischemic attack (RR=2.9, P<0.001) were independently associated with increased stroke risk. Regular consumption of >/=14 alcohol-containing drinks per week was associated with reduced stroke risk (adjusted RR=0.4, P=0.04). Among SPAF III participants, estrogen hormone replacement therapy was associated with a higher risk of ischemic stroke (adjusted RR=3.2, P=0.007). With the use of these variables, a risk stratification scheme for primary prevention separated participants into those with high (7.1%/y, 22% of the cohort), moderate (2.6%/y, 37% of the cohort), and low (0.9%/y, 41% of the cohort) rates of stroke. Ischemic strokes in low-risk participants were less often disabling (P<0.001). CONCLUSIONS: Patients with AF who have high and low rates of stroke during treatment with aspirin can be identified. However, validation of our risk stratification scheme is necessary before it can be applied with confidence to clinical management. Postmenopausal estrogen replacement therapy and moderate alcohol consumption may additionally modify the risk of stroke in AF, but these findings require confirmation.
Asunto(s)
Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Isquemia Encefálica/etiología , Trastornos Cerebrovasculares/etiología , Anciano , Consumo de Bebidas Alcohólicas/fisiopatología , Trastornos Cerebrovasculares/prevención & control , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Terapia de Reemplazo de Estrógeno/efectos adversos , Femenino , Humanos , Masculino , Análisis Multivariante , Análisis de Regresión , Factores de Riesgo , Warfarina/administración & dosificación , Warfarina/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Thoracic aortic plaque identified by transesophageal echocardiography heightens the risk of stroke associated with atrial fibrillation (AF). We sought to identify the prevalence, predictors, and implications of aortic plaque in patients with nonvalvular AF. METHODS: Thoracic aortic plaque was prospectively sought in 770 persons with AF with the use of transesophageal echocardiography and classified as simple or complex on the basis of thickness >/=4 mm, ulceration, or mobility. Clinical and echocardiographic features of thromboembolism were correlated by multivariate analysis. RESULTS: Aortic plaque was detected in 57% of the cohort, and complex plaque was detected in 25%. Both were found more frequently in the descending than in the proximal aorta. Potentially etiologic patient characteristics independently associated with complex plaque included advanced age, history of hypertension, diabetes, and past or present tobacco use. Comorbidities associated with aortic plaque were prior thromboembolism, increased pulse pressure, ischemic heart disease, stenosis or sclerosis of the aortic valve, mitral annular calcification (>10%), elevated serum creatinine concentration, spontaneous echo contrast in the left atrium or appendage, and left atrial appendage thrombus. The prevalence of complex plaque in patients aged <70 years with <10% mitral annular calcification, without ischemic heart disease, or without pulse pressure >/=65 mm Hg was 4% (95% CI, 1% to 6%). CONCLUSIONS: Aortic plaque is prevalent in patients with AF and is associated with atherosclerosis risk factors and with left atrial stasis or thrombosis, which are themselves independent stroke risk factors. Since the predominant location of complex plaque was in the descending aorta, the role of aortic plaque as a source of embolism in AF is uncertain.