Anticoagulation for valvular heart disease in community-based practice.

Little is known about patients who receive oral anticoagulation for valvular heart disease (VHD) in community-based practice. It was this study's objective to describe the characteristics, management, and outcomes of patients anticoagulated for VHD, compared to patients anticoagulated for atrial fibrillation (AF). We used a nationally-representative cohort of community-based anticoagulation care in the United States. Data collected included indications for therapy, demographics, selected comorbid conditions, international normalised ratio (INR) target ranges, INR control, and clinical outcomes. We identified 1,057 patients anticoagulated for VHD (15.6% of the overall cohort) and 3,396 patients anticoagulated for AF (50.2%). INR variability was similar between the two groups (0.64 vs. 0.69, p = 0.80). Among patients with aortic VHD, for whom a standard (2-3) target INR range is recommended, 461 (84%) had a high target range (2.5-3.5), while 95 (16%) had a standard target range. VHD patients had a higher rate of major haemorrhage compared to AF patients (3.57 vs. 1.78 events per 100 patient-years, incidence rate ratio 2.02, 95% CI 1.33 - 3.06). The rate of stroke/systemic embolus was similar between groups (0.67 vs. 0.97 events per 100 patient-years, incidence rate ratio 0.71, 95% CI 0.32 - 1.57). In our community-based study, approximately 15.6% of patients receiving warfarin were anticoagulated for VHD. VHD patients achieved similar anticoagulation control to patients with AF, as measured by INR variability. Nevertheless, the rate of major haemorrhage was elevated among VHD patients compared to AF patients; this finding requires further investigation.

Warfarin dose management affects INR control.

BACKGROUND: Little is known about how patterns of warfarin dose management contribute to percentage time in the therapeutic International Normalized Ratio (INR) range (TTR). OBJECTIVES: To quantify the contribution of warfarin dose management to TTR and to define an optimal dose management strategy. PATIENTS/METHODS: We enrolled 3961 patients receiving warfarin from 94 community-based clinics. We derived and validated a model for the probability of a warfarin dose change under various conditions. For each patient, we computed an observed minus expected (O - E) score, comparing the number of dose changes predicted by our model to the number of changes observed. We examined the ability of O - E scores to predict TTR, and simulated various dose management strategies in the context of our model. RESULTS: Patients were observed for a mean of 15.2 months. Patients who deviated the least from the predicted number of dose changes achieved the best INR control (mean TTR 70.1% unadjusted); patients with greater deviations had lower TTR (65.8% and 62.0% for fewer and more dose changes respectively, Bonferroni-adjusted P < 0.05/3 for both comparisons). On average, clinicians in our study changed the dose when the INR was 1.8 or lower/3.2 or higher (mean TTR: 68%); optimal management would have been to change the dose when the INR was 1.7 or lower/3.3 or higher (predicted TTR: 74%). CONCLUSIONS: Our observational study suggests that INR control could be improved considerably by changing the warfarin dose only when the INR is 1.7 or lower/3.3 or higher. This should be confirmed in a randomized trial.

Warfarin for atrial fibrillation in community-based practise.

BACKGROUND: Previous studies of anticoagulation for atrial fibrillation (AF) have predominantly occurred in academic settings or randomized trials, limiting their generalizability. OBJECTIVE: To describe the management of patients with AF anticoagulated with warfarin in community-based practise. METHODS: We enrolled 3396 patients from 101 community-based practises in 38 states. Data included demographics, comorbidities, and International Normalized Ratio (INR) values. Outcomes included time in therapeutic INR range (TTR), stroke, and major hemorrhage. RESULTS: The mean TTR was 66.5%, but varied widely among patients: 37% had TTR above 75%, while 34% had TTR below 60%. The yearly rates of major hemorrhage and stroke were 1.90 per 100 person-years and 1.00 per 100 person-years. Four percent of patients (n = 127) were intentionally targeted to a lower INR, and spent 42.7% of time with an INR below 2.0, compared to 18.8% for patients with a 2.0-3.0 range (P < 0.001). Mean TTR for new warfarin users (57.5%) remained below that of prevalent users through the first six months. Patients with interruptions of warfarin therapy had lower TTR than all others (61.6% vs. 67.2%, P < 0.001), which corrected after deleting low peri-procedural INR values (67.0% vs. 67.4%, P = 0.73). CONCLUSIONS: Anticoagulation control varies widely among patients taking warfarin for AF. TTR is affected by new warfarin use, procedural interruptions, and INR target range. In this community-based cohort of predominantly prevalent warfarin users, rates of hemorrhage and stroke were low. The risk versus benefit of a lower INR target range to offset bleeding risk remains uncertain.

Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.

CONTEXT: Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described. OBJECTIVE: To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050. DESIGN, SETTING, AND PATIENTS: Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997. MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between 1995-2050. RESULTS: A total of 17 974 adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older. Among persons aged 50 years or older, prevalence of atrial fibrillation was higher in whites than in blacks (2.2% vs 1.5%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older. CONCLUSIONS: Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation.

Implications of stroke risk criteria on the anticoagulation decision in nonvalvular atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.

BACKGROUND: Warfarin dramatically reduces the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) but increases the likelihood of bleeding. Accurately identifying patients who need anticoagulation is critical. We assessed the potential impact of prominent stroke risk classification schemes on this decision in a large sample of patients with NVAF. METHODS AND RESULTS: We used clinical and electrocardiographic databases to identify 13 559 ambulatory patients with NVAF from July 1996 through December 1997. We compared the proportion of patients classified as having a low enough stroke risk to receive aspirin using published criteria from the Atrial Fibrillation Investigators (AFI), American College of Chest Physicians (ACCP), and the Stroke Prevention in Atrial Fibrillation Investigators (SPAF). In this cohort, AFI criteria classified 11% as having a low stroke risk, compared with 23% for ACCP and 29% for SPAF (kappa range, 0.44 to 0.85). This 2- to-3-fold increase in low stroke risk patients by ACCP and SPAF criteria primarily resulted from the inclusion of many older subjects (65 to 75 years+/-men >75 years) with no additional clinical stroke risk factors. CONCLUSIONS: The age threshold for assigning an increased stroke risk has a dramatic impact on whether to recommend warfarin in populations of patients with NVAF. Large, prospective studies with many stroke events are needed to precisely determine the relationship of age to stroke risk in AF and to identify which AF subgroups are at a sufficiently low stroke risk to forego anticoagulation.

IL-4 enhances IL-10 gene expression in murine Th2 cells in the absence of TCR engagement.

Both IL-4 and IL-10 are regulatory cytokines produced by Th2 cells that can down-regulate cell-mediated immune responses. The studies reported here examine the influence of various cytokines in the regulation of T cell IL-10 production. The results indicate that IL-10 gene expression by TCR transgenic Th2 cells is significantly up-regulated by IL-4 in the absence of TCR signals. IL-4 enhances both IL-10 mRNA levels and secreted protein, and this effect is not related to enhanced mRNA stability. TCR-mediated IL-10 gene expression is inhibited by cyclosporin A, but IL-4-mediated IL-10 expression is not. IL-4 also enhances IL-13 mRNA levels, to a lesser extent than IL-10, but does not significantly effect the expression of other cytokine mRNAs. Furthermore, IL-4 does not significantly enhance IL-10 expression in Th1 cells. IL-2 also enhances effector cytokine production in the absence of TCR signals, but in a subset nonspecific manner, increasing both Th2 IL-4 mRNA and Th1 IFN-gamma mRNA. These data suggest that Th2 IL-4 production may contribute to the down-regulation of immune responses by directly enhancing Th2 IL-10 production. In addition, the data clearly demonstrate that exogenous cytokines can significantly influence effector cytokine production by effector T cells without the requirement for TCR signals.

Human endothelial cell costimulation of T cell IFN-gamma production.

In this report, we show that human endothelial cells (EC) provide costimulatory signals to mitogen-activated CD4+ T cells to augment IFN-gamma production. We also show that EC can enhance responsiveness of the T cells to IL-12. While IL-12 has no effect on IFN-gamma production by cultured CD4+ T cells in the absence of EC, addition of IL-12 to T cell-EC cocultures augments IFN-gamma production by as much as fivefold. Separation of T cells from EC by a semipermeable membrane inhibits the effect of EC and IL-12 on IFN-gamma production. Anti-LFA-3 Abs, in the absence or presence of IL-12, inhibit EC costimulation of IFN-gamma production by up to 50%, while Abs to intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), LFA-1, and very late antigen-4 (VLA-4) have relatively little effect. Pretreatment of T cells with conditioned medium from T cell-EC cocultures, or with IL-2 or IL-1 alpha similarly primes CD4+ T cells for the costimulatory effect of IL-12 on IFN-gamma production. EC costimulation of IFN-gamma production is inhibited by cyclosporine. However, in the presence of IL-12 there is a marked resistance to this inhibitory effect, suggesting that the IL-12-induced costimulatory pathway is distinct from the costimulatory pathway activated by endothelium alone. Our data are consistent with the hypothesis that, as a consequence of interactions with endothelium, T cells that migrate into an inflammatory site are primed to have enhanced responses to Ag and cytokine(s), such as IL-12, that influence T cell-cytokine production.