Chronic Nonvalvular Atrial Fibrillation Research Articles

Comparison of Frequency of Thromboembolic Events and Echocardiographic Findings in Patients With Chronic Nonvalvular Atrial Fibrillation and Coarse Versus Fine Electrocardiographic Fibrillatory Waves

In patients with nonvalvular atrial fibrillation, the electrocardiographic fibrillatory wave reflects the structural and electrical remodeling of the atria. This study examined whether the fibrillatory wave amplitude could predict the risk of thromboembolism and demonstrated that this amplitude was related to the duration of atrial fibrillation. We also showed that the presence of fine fibrillatory waves (<1 mm in amplitude) could predict the thromboembolic potential in patients with chronic nonvalvular atrial fibrillation.

Conventional wisdom vs reality in stroke prevention

The economist Galbraith distinguishes the divergence between “reality” and “approved belief.”1 Belief seems sensible and will later masquerade as “conventional wisdom.” Entrepreneurs cultivate their own version of approved belief and reap rewards disregarding the impact on company or shareholder. Similarity exists between “common-sense” business practices and time-honored medical therapeutics. “Experience” recommended tonsillectomy. Clinical trials in Pittsburgh schools introduced “reality,” sparing tonsillectomy to millions. “Conventional wisdom” directed weeks of bed rest after myocardial infarction (MI). The practice stopped when trials counted reduced deaths with early ambulation. In stroke prevention, randomized trials, unavailable to commerce, have introduced reality or rejection for successive innovative strategies. Vascular risks were identified and many management strategies perfected. Collectively they are front-line therapy for all stroke-threatened patients. Anticoagulants exemplify the uncertainties in medical practice based on unproven hypotheses. Indications for warfarin and heparin lay in the shadows for half a century. Untold millions received them. Reality emerged from belated clinical trials: patients with chronic nonvalvular atrial fibrillation are obligatory recipients of warfarin; patients with noncardiogenic ischemic stroke do not benefit. Conventional wisdom was dealt a body-blow. Platelet inhibitors fared better. In the 1960s they were discovered to alter platelet function. Scientists studying the antiplatelet activity of aspirin and sulfinpyrazone insisted upon randomized trials before “approved belief” could emerge.2 The claim that a pain drug could prevent thrombotic disease was viewed skeptically. Larger trials included patients with cerebral and coronary artery symptoms. Reality was achieved: aspirin emerged as the front-line platelet inhibitor for preventing ischemic stroke and MI. The era of platelet inhibition was established. Other platelet inhibitors were approved following randomized trials commercially conducted with data guarded by industry. Their analyses and data management illustrate the need to interpret cautiously the reports of trials even though randomized. The combination of dipyridamole (DP) 225 mg + …

Quality of Anticoagulation Control and Costs of Monitoring Warfarin Therapy among Patients with Atrial Fibrillation in Clinic Settings: A Multi-Site Managed-Care Study

Warfarin is recommended for prevention of stroke in patients with atrial fibrillation who are at moderate or high risk, but requires intensive management to achieve safe and optimal anticoagulation control. Anticoagulation clinics are often used to administer warfarin therapy more effectively. To collect data from multiple sites and assess the quality and costs associated with anticoagulation clinic services. A random sample of 600 adults with chronic nonvalvular atrial fibrillation (CNVAF) receiving warfarin was selected from anticoagulation clinics affiliated with 3 health plans. Patients were identified between 1996 and 1998 and followed for up to one year. We assessed the proportion of time that international normalized ratio (INR) values were within the recommended range (2.0-3.0) and the costs of anticoagulation clinic care. Patients had an average of 18 clinic contacts over a mean duration of follow-up of 10.5 months. On average, patients were within the recommended INR range 62% of this time, with 25% of days below range and 13% above range. The mean per-patient cost of warfarin monitoring over the follow-up period averaged $261 at site A, $305 at site B, and $205 at site C (in 2003 US$). Mean costs for patients treated for one full year were $288, $339, and $216, respectively. In 3 geographically diverse health plans, anticoagulation clinics provided a generally higher quality of control than previously reported in other observational studies. This study highlights the costs of obtaining this level of control.

Anticoagulation therapy in patients with chronic atrial fibrillation: a retrospective claims data analysis

ABSTRACTObjectives: This study assessed the risk of thromboembolic events and bleeding complications among atrial fibrillation patients.Methods: A cohort of patients with chronic non-valvular atrial fibrillation were identified from medical claims (diagnosis codes 427.31 and 427.32). Subjects were identified from 1 January 1998–31 December 2000 and were continuously enrolled for 6 months prior to the first occurring atrial fibrillation medical claim. Cox proportional hazards analysis with time varying covariates was used for the event analysis.Results: Of 6764 subjects retained for analysis, 3541 (52.4%) were exposed to warfarin. Adjusting for baseline characteristics, warfarin exposure was associated with lower likelihood of an arterial thromboembolic event compared to no exposure (HR: 0.710, CI: 0.540–0.934). No benefit was found in the use of warfarin in the prevention of intracranial events (HR: 1.119, CI: 0.929–1.349). Use of warfarin increased the risk of minor bleeding events (HR: 3.600, CI: 2.537–5.109), and all bleeding events (HR: 1.502, CI: 1.289–1.749).Conclusions: The risk of arterial thromboembolic events was associated with warfarin exposure as expected. An increase in the risk of minor and total bleeding events among patients treated with warfarin was observed. The results of this study suggest that there may be a gap between the clinical trial and coagulation clinic performance of warfarin in reducing the risk of thromboembolic events versus what is achievable in general practice.

Atrial fibrillation and hypercoagulability: dependent on clinical factors or/and on genetic alterations?

It is well known that atrial fibrillation is associated with high incidence of thromboembolic events, propably due to a prothrombotic or hypercoagulable state. However, it is unclear whether or not there is any difference of this prothrombotic state in the clinical subgroups of atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. From the other side the role of the arrhythmia duration on the changes of coagulative variables in atrial fibrillation patients is not clearly enough. The contribution of genetic and functional alterations in factors of the coagulation and fibrinolytic pathways (that is hemostatic risk factors) to the development of hypercoagulation state in atrial fibrillation requires clarification. We investigated therefore (1) if there are differences in the prothrombotic state between patients with different clinical status of the arrhythmia, (2) if the arrhythmia duration per se could be an independent determinant of the prothrombotic state in all atrial fibrillation patients and (3) if coexistent genetic alterations in haemostatic risk factors in patients with atrial fibrillation could contribute to the development of prothrombotic abnormalities. Over a period of 23 months, we studied 55 patients with chronic non-valvular atrial fibrillation. We recruited 18 consecutive patients (13 men, mean age 59 +/- 10 years) with paroxysmal atrial fibrillation 17 patients (11 men, mean age 61 +/- 7 years) with persistent atrial fibrillation who underwent elective successful DC and remained in sinus rhythm at the 3 month visit and 20 patients (14 men mean age 64 +/- 9) with permanent atrial fibrillation. Blood results were compared to 17 age-sex- and race-matched controls. The prothrombotic state was quantified by measurement of plasma levels of fibrinogen, soluble P -selectin (an index of platelet activation) and von Willebrand factor (a marker of endothelial dysfunction). We assessed the frequencies of factor V Leiden and prothrombin variant G20210A to determine whether particular inherited haemostatic risk factors may have contribution to the development of prothrombotic state in atrial fibrillation patients. Permanent atrial fibrillation was associated with significant raised levels of von Willebrand factor, fibrinogen levels and soluble P -selectin compared to matched controls (all p < 0.001) and matched patients with paroxysmal and permanent AF (all p ranged between <0.003 and <0.002). Patients with persistent atrial fibrillation had significantly elevated von Willebrand factor levels (p = 0.0064) and fibrinogen levels (p = 0.002), but not Soluble P -selectin (p = 0.509). when compared to controls. Patients with paroxysmal atrial fibrillation had significantly elevated levels of P -selectin (p = 0.005) and fibrinogen (p = 0.003), but not von Willebrand factor (p =.0.61) compared to controls. Stepwise multiple regression analyses demonstrated that the arrhythmia duration (approximately 3 years) was an independent predictor of abnormal von Willebrand factor, fibrinogen and soluble P -selectin levels. Restoration of sinus rhythm in paroxysmal atrial fibrillation subgroup and successful electrical cardioversion of patients with permanent fibrillation atrial fibrillation did not significantly alter levels of the affected factors. The frequency of factor V Leiden was 8.9 in all studied patients with atrial fibrillation, versus 2.4% in the control group (odds ratio [OR] 4.6 [95% confidence (CI) 1.4-17.5], p = 0.02). The frequency of the prothrombin variant G20210A was 6.4.% compared with control group 1.6% (OR 4.9 [95% confidence interval (CI) 1.2-2.9], p = 0.04). There was a trend towards an increased frequency of factor V Leiden and/or prothrombin variant G20210A in patients age <55 years and in patients living at a particular area of Thrace mountains. Our results showed that there were significant differences in the prothrombotic state when patients with paroxysmal, and persistent atrial fibrillation were compared to matched that there were significant differences in the prothrombotic state when patients with paroxysmal, and persistent atrial fibrillation were compared to matched patients with permanent atrial fibrillation and controls in sinus rhythm. The duration of the arrhythmia (about 3 years) was an independent predictor of abnormal measured factors. We found for the first time that some genetic alterations in haemostatic risk factors could be coexist in atrial fibrillation patients and may be a contributor to the development of hypercoagulability in atrial fibrillation patients.

Left Atrial Appendage Function and Abnormal Hypercoagulability in Patients With Atrial Flutter

The prevalence of thromboembolism might be higher than previously recognized in patients with atrial flutter (AFL) based on findings of transesophageal echocardiography (TEE). To evaluate the potential prothrombotic state in patients with AFL, TEE findings and hemostatic markers were compared among patient groups with AFL, normal sinus rhythm (NSR) and chronic nonvalvular atrial fibrillation (AF). Cross-sectional study at a university hospital. In 28 patients (mean age, 63 years) with AFL, 58 patients (mean age, 66 years) with AF, and 27 patients (mean age, 61 years) with NSR who underwent TEE, plasma levels of markers for platelet activity (platelet factor 4 and beta-thromboglobulin [beta-TG]), thrombotic status (thrombin-antithrombin III complex and prothrombin fragments 1 and 2) and fibrinolytic status (d-dimer and plasmin-alpha(2)-plasmin inhibitor complex) were determined. Left atrial appendage (LAA) blood flow velocity in patients with AFL was higher (p < 0.05) than that in patients with AF, but was lower (p < 0.05) than that in patients with NSR (AF, 25 +/- 2; AFL, 44 +/- 4; NSR, 60 +/- 4 cm/s). Dense left atrial spontaneous echo contrast (SEC) was found in 4 patients (14%) with AFL and 16 patients (28%) with AF. There was no significant difference in plasma levels of hemostatic markers between the AFL group and the NSR group. AFL patients with impaired LAA function (LAA flow < 30cm/s, dense SEC, or both), however, showed higher level of d-dimer and beta-TG than those without impaired LAA function (d-dimer, 1.9 +/- 0.6 microg/mL vs 0.4 +/- 0.1 microg/mL; beta-TG, 73 +/- 17 ng/mL vs 33 +/- 5 ng/mL, p < 0.05). Patients with AFL as a whole are not in the prothrombotic state as compared with those with AF. However, patients with AFL and impaired LAA function are at potentially high risk for thromboembolism and might require anticoagulation.

Un protocolo prospectivo permite incrementar la utilización de anticoagulación oral en pacientes con fibrilación auricular crónica no valvular

Observational studies have shown that oral anticoagulants (OAC) prescription is suboptimal in patients with nonvalvular atrial fibrillation (NVAF). Our objective was to evaluate the usefulness of a prospective protocol for increasing OAC usage in these patients. From 1 February 2000 until 31 October 2002 we enrolled all patients with chronic NVAF seen in two outpatient cardiology clinics, excluding candidates for cardioversion. Each patient was studied to identify cardioembolic risk factors (CERF) and contraindications for OAC. Anticoagulation was suggested to all patients with > or =2 CERF and without contraindications for OAC. The decision to prescribe OAC was made by the physician in charge when there was only one CERF. 721 patients fulfilled the inclusion criteria. Mean age was 73 +/- 8 years; 44% were men. In most cases NVAF was related with hypertension (57%), followed by no structural heart disease (25%) or ischemic heart disease (9%). The most frequent CERFs were hypertension (66%), age > or =75 years (45%) and diabetes (24%). A total of 663 patients had > or =1 CERF (92%), and 125 (19%) of these presented at least one contraindication for OAC. Of the 538 remaining patients (90%), 485 (67% of the whole series) were treated with anticoagulation. Of the patients with > or =2 CERF and without contraindications for OAC, 95% were treated. A prospective protocol for use in the outpatient cardiology clinic allows to prescribe OAC in a large percentage of patients with NVAF.

Relationship between left atrial appendage function and left atrial thrombus in patients with nonvalvular chronic atrial fibrillation and atrial flutter.

The relationship between the left atrial appendage (LAA) function, as assessed by transesophageal echocardiography, and the incidence of left atrial thrombus was evaluated in 62 patients with nonvalvular chronic atrial fibrillation (AF; n=50) and atrial flutter (AFL; n=12). It was hypothesized that in both AF and AFL not only the LAA flow velocity (LAAFV), but also the frequency of the LAA movement (the LAA flow time, LAAFT) is a major contributing factor to thrombus formation. LAAFT was defined as the average duration of LAA flow with emptying and filling waves. The patients with AF were divided into 2 groups: lone AF (n=14) and non-lone AF (n=36). LAA thrombus was found in 6 patients with none-lone AF. LAAFV was lower and LAAFT was shorter in patients with thrombus as compared with patients without thrombus (12.0+/-2.2 cm/s vs 24.1+/-10.6 cm/s, 68.7+/-1.5 ms vs 72.9+/-3.3 ms, p<0.01, respectively). Patients with AFL had higher LAAFV and longer LAAFT than those with chronic AF. The present data suggest that, in addition to LAAFV, LAAFT characterized LAA function and might serve as a predictor of thrombus formation in chronic AF. With respect to LAA function, patients with lone AF or AFL are at low risk for thrombus formation.

Short-term effects of sinus rhythm restoration in patients with lone atrial fibrillation: a hormonal study.

It is well known that atrial fibrillation can lead to heart failure, and is attributed to rapid ventricular rate (tachycardia-induced cardiomyopathy). Some recent studies suggest the possible existence of an intrinsic left-ventricular factor related to atrial fibrillation, irrespective of other elements. In order to demonstrate the implication of this factor, we measured B-type Natriuretic Peptide, known as a functional marker of left-ventricular dysfunction, in 40 consecutive patients with chronic non-valvular atrial fibrillation, with low ventricular rate and absence of clinical heart failure or echocardiographic left-ventricular dysfunction. In all patients, Brain Natriuretic Peptide (BNP) plasma level was high and dramatically decreased 24 h after external electrical cardioversion (61.4 pg/ml before cardioversion, 23.5 pg/ml 1 day after cardioversion, P<0.002). Our study demonstrates that atrial fibrillation, in absence of high ventricular rate, induces an asymptomatic cardiac alteration that is not detectable by echocardiography.

Effects of left ventricular systolic dysfunction on left atrial appendage and left atrial functions in patients with chronic nonvalvular atrial fibrillation

Objective — It has been claimed that left ventricular (LV) systolic dysfunction impairs left atrial (LA) and left atrial appendage (LAA) functions. In this study, we compared the LA and LAA function parameters in patients with chronic nonvalvular atrial fibrillation (AF) with and without LV systolic dysfunction.Methods and results — The study population consisted of 28 patients with chronic nonvalvular AF.Group I consisted of 12 patients with LV systolic dysfunction (mean age: 61 ± 14 years; LV ejection fraction: 44 ± 6%), group II of 16 patients with normal LV systolic function (mean age: 52 ± 15 years; LV ejection fraction: 65 ± 3%). LV ejection fraction (EF) was measured by echocardiography utilizing bi-plane area length method.The following LA and LAA transoesophageal echocardiography parameters were obtained: 1) LA diameter, 2) LAA ejection velocity, 3) LAA filling velocity, 4) LAA ejection fraction, 5) pulmonary venous (PV) systolic velocity, 6) PV diastolic velocity, 7) PV systolic velocity/diastolic velocity ratio.The left atrium diameter was significantly larger in group I than in group II (4.7 ± 0.7 cm vs. 3.8 ± 0.6 cm, p < 0.05). The LAA ejection velocity and LAA ejection fraction were significantly lower in group I than in group II (22.6 ± 15.5 cm/s vs 37.5 ± 11.3 cm/s and 26.9 ± 20.8% vs. 41.3 ± 10.9%, p < 0.05 for both comparisons). The PV systolic velocity and PV systolic velocity/diastolic velocity ratio were significantly smaller in group I than in group II (26.2 ± 14.8 cm/s vs. 51.5 ± 22 cm/s and 0.7 ± 0.6 vs. 1.2 ± 0.5, p < 0.05 for both comparisons). Although decreased LAA filling and PV diastolic velocities were determined in group I, no significant difference existed between groups I and II.Thrombus and/or spontaneous echo contrast (SEC) in the LA and/or LAA were more frequent in group I (75% vs. 18%, p < 0.05).Conclusion — These results indicate that LV systolic dysfunction impairs various LA and LA function parameters and is associated with an increased frequency of SEC and/or LA thrombus in patients with chronic nonvalvular AF.

Letters to the Editor

Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. They should not exceed 1000 words (excluding references) and may be subject to editing or abridgment. Please submit letters in duplicate, typed double-spaced. Include a fax number for the correspondling author and a completed copyright transfer agreement form (published in the January and July issues) . To the Editor: We wish to congratulate Hart and Halperin1 on their excellent overview of the current “concepts and controversies” surrounding atrial fibrillation (AF) and stroke. In discussing the formation of thrombus within the left atrial appendage (LAA), they focus a large part of their discussion on the issue of blood stasis in the LAA that occurs in AF, suggesting this mechanism of thrombogenesis to perhaps be of greatest importance, although conceding that “many questions remain about the formation and embolism of left atrial …

Does acute-phase beta blockade reduce left atrial appendage function in patients with chronic nonvalvular atrial fibrillation?

To investigate whether acute-phase beta-blocker therapy has a harmful effect on left atrial appendage (LAA) function in patients with chronic nonvalvular atrial fibrillation by transesophageal echocardiography (TEE), we evaluated 21 patients with normal left ventricular systolic function and a poorly controlled ventricular rate, despite the use of digoxin. Baseline parameters that were obtained included heart rate, blood pressure, LAA emptying velocities, and left atrial spontaneous echo contrast intensity. Then, each patient was given a bolus dose of 5 mg metoprolol. Ten minutes later, a second set of assessments was performed. After the first TEE studies, each patient began treatment with metoprolol (50 mg orally twice daily for 1 week). A second TEE study was performed after 1 week of continuous oral metoprolol therapy at maintenance dose, and values were again determined. The average resting apical heart rate was 91 ± 7 bpm. As expected, beta-blocker therapy showed a marked decrease in heart rate at 10 minutes (79 ± 6 bpm, P <.001) and at 1 week (71 ± 4 bpm, P <.001). Beta-blocker therapy caused a significant reduction in systolic and diastolic blood pressures (144 ± 16 / 93 ± 6 mm Hg at baseline, 137 ± 16 / 87 ± 9 mm Hg at 10 minutes, and 135 ± 12 / 86 ± 8 mm Hg at 1 week, P <.001). With the beta-blocker therapy, the baseline transesophageal Doppler parameter of LAA emptying velocities (at baseline 24 ± 7 cm/s) fell significantly at 10 minutes (19 ± 7 cm/s, P <.001) and at 1 week (17 ± 6 cm/s, P <.001) after initiation of beta-blocker therapy. After a bolus of metoprolol, spontaneous echo contrast intensity did not change in any patients, but 1 week later, it increased in 1 patient. In 2 patients who had not been found to have an LAA thrombus at baseline TEE study, the second TEE examination demonstrated new thrombi in the LAA. In conclusion, our findings suggest that in patients with chronic nonvalvular atrial fibrillation who have normal left ventricular systolic function and a poorly controlled ventricular rate despite the use of digoxin, acute-phase beta blockade may have a harmful effect on LAA function. (J Am Soc Echocardiogr 2001;14:194-9.)

Role of transesophageal echocardiography in the prediction of thromboembolism in patients with chronic nonvalvular atrial fibrillation.

The purpose of this study was to determine whether parameters derived from transesophageal echocardiography (TEE) could predict thromboembolism in patients with chronic nonvalvular atrial fibrillation (AF). Eighty-nine patients, mean age 66+/-9 years, who underwent TEE in 1996 to 1999 were studied. The clinical endpoint was a thromboembolic event, including transient ischemic attack (TIA). Sixty-seven patients (75%) were anticoagulated with warfarin after TEE. After a follow-up period of 29+/-10 months, 1 patient died suddenly, 4 had a thromboembolism, and 3 had a TIA; the annual embolic event rate was 3.3%. Left atrial appendage (LAA) thrombus (86% vs 17%, p<0.001), LAA dysfunction (LAA velocity <20 cm/s; 71% vs 25%, p=0.009), and severe LA spontaneous echo contrast (29% vs 2%, p=0.002) were more prevalent in patients with an embolic event than in those without. In patients with LAA thrombus, the annual event rate was 11% as compared with 1.2% in those without (p=0.004). On the Cox proportional hazards model analysis, LAA thrombus (chi-square 7.0, p=0.008), severe LA spontaneous echo contrast (chi-square 7.0, p=0.008), and LAA dysfunction (chi-square 5.9, p=0.015) were significantly related to thromboembolism. Multivariate analysis revealed that LAA thrombus (chi-square 5.5, p=0.019) and LAA dysfunction (chi-square 4.0, p=0.045) were the independent predictors. In conclusion, TEE parameters, particularly the presence of LAA thrombus, can be used to assess thromboembolic potential in patients with chronic nonvalvular AF.

Effect of degree of blood pressure on the hypercoagulable state in chronic atrial fibrillation

To investigate the hypothesis that higher levels of blood pressure would further promote the hypercoagulable state in atrial fibrillation (AF) by increasing the degree of hemostatic abnormalities, we studied 82 consecutive patients with chronic nonvalvular AF who were not taking antithrombotic therapy. Patients with AF had higher levels of plasma fibrin D-dimer, von Willebrand factor, and fibrinogen than controls in sinus rhythm, and no differences between tertiles of either systolic, diastolic, or mean blood pressure were found, suggesting other mechanisms may be contributing to the hypercoagulable state in AF.

Integrated Backscatter Assessment of Left Atrial Spontaneous Echo Contrast in Chronic Nonvalvular Atrial Fibrillation: Relation with Clinical and Echocardiographic Parameters

Integrated backscatter (IB) provides the quantitative assessment of left atrial spontaneous echo contrast (SEC). The IB intensity of the left atrial cavity relative to the left ventricular cavity is related to atrial thrombus in patients with atrial fibrillation (AF) or sinus rhythm. However, little is known about the relation between the quantitative SEC value of the left atrial cavity and variables implying thromboembolism in nonvalvular AF. To examine this relation, we performed transesophageal echo-cardiography with IB analysis in 65 patients with chronic nonvalvular AF. The quantitative SEC value of the left atrial cavity was defined as the difference between atrial IB intensity and ventricular IB intensity (corrected IB intensity). The corrected IB intensity was correlated with the left atrial dimension (r = 0.25, P =.049), the left atrial appendage velocity (r = –0.41, P <.001), and the duration of AF (r = 0.23, P =.023). The corrected IB intensity was higher in patients who had a history of hypertension (3.2 ± 2.2 dB versus 2.0 ± 1.6 dB, P =.018), SEC (3.9 ± 1.9 dB versus 1.4 ± 1.1 dB, P =.002), and left atrial thrombus (4.5 ± 2.7 dB versus 2.2 ± 1.7 dB, P <.001) when compared with those who did not have these abnormalities. The corrected IB intensity was significantly lower in patients with significant mitral regurgitation than in those without it (1.1 ± 1.2 dB versus 2.7 ± 2.0 dB, P =.036). When the cutoff value of the corrected IB intensity was set at ≥2.0 dB, the sensitivity for left atrial thrombus was 78% and the specificity was 55%. In patients with chronic nonvalvular AF, the quantitative SEC value of the left atrial cavity depends on the duration of AF as well as the left atrial dimension and appendage velocity. Although IB may be capable of identifying patients with higher risk of cardiogenic embolism, a large-scale prospective study is needed to actually establish this. (J Am Soc Echocardiogr 2000;13:666-73.)

Adverse outcomes and predictors of underuse of antithrombotic therapy in medicare beneficiaries with chronic atrial fibrillation.

Antithrombotic therapy can prevent strokes and transient ischemic attacks (TIAs) in carefully selected patients who have chronic nonvalvular atrial fibrillation (NVAF). Our objectives were 3-fold: to document the use of warfarin and aspirin therapy in Missouri Medicare beneficiaries with chronic NVAF; to identify factors associated with warfarin and aspirin underuse; and to determine the association between prescription of warfarin and aspirin at hospital discharge and adverse outcomes in this elderly, frail population. We linked chart reviews from all Missouri hospitals to Medicare claims data from 1993 to 1996. From chart reviews, we documented Medicare beneficiaries' demographic factors, comorbid conditions, and antithrombotic therapy prescribed at the time of hospital discharge. From Medicare claims, we determined the date of outcomes-death from any cause or hospitalization for an ischemic event (a stroke, a TIA, or a myocardial infarction). Only 328 (55%) of the 597 Medicare beneficiaries were prescribed antithrombotic therapy at hospital discharge: 34% received warfarin and 21% received aspirin. Advanced age, female gender, and rural residency predicted underuse of antithrombotic therapy. After controlling for these factors, as well as stroke risk factors and contraindications to anticoagulation, the prescription of warfarin was associated with a 24% relative risk reduction (RRR) in adverse outcomes (P=0.003). Prescription of aspirin was associated with a nonsignificant 5% RRR in these events (P=0.56). The underuse of antithrombotic therapy in Medicare beneficiaries who have NVAF is associated with measurable adverse outcomes. The benefit of warfarin therapy may extend to frail, elderly patients, a group that was excluded from randomized controlled trials. The role of antiplatelet therapy in this population deserves further study because many of these patients have relative contraindications to warfarin.

Structural Remodeling of the Left Atrial Appendage in Patients with Chronic Non-Valvular Atrial Fibrillation: Implications for Thrombus Formation, Systemic Embolism, and Assessment by Transesophageal Echocardiography

Left atrial appendage (LAA) is frequently the site of thrombus formation in patients with chronic atrial fibrillation (AF). Transesophageal echocardiography and hematologic studies have identified blood flow stasis (spontaneous echogenic contrast) and abnormal coagulation (increased serum fibrinogen) as important predisposing factors to formation of LAA thrombi. However, the third component of the Virchow's triad, i.e., endothelial abnormalities, has not been adequately studied. Accordingly, we studied, at necropsy, the LAA morphology in 46 hearts of patients with ( n = 22) and without ( n = 24) chronic AF. Compared to patients without AF, those with AF had significantly larger LAA volumes (1.7% 1.1 vs. 5.4% 3.7 mL, p = 0.0002), and larger luminal surface area of the bisected LAA (4.4% 1.8 vs. 7.1% 4.5 cm 2, p = 0.01). However, both the absolute and relative surface area of the transected pectinate muscles were reduced in patients with AF (2.6% 1.1 vs. 1.8% 1.0 cm 2, p = 0.02 and 38% 15 vs. 21% 14%, p = 0.0003). In addition, in most patients (73%) with chronic AF, the LAA showed significant endocardial thickening with fibrous and elastic tissue (endocardial fibroelastosis) compared to those without AF (13%, p < 0.0001). Endocardial fibroelastosis resulted in a smooth LAA luminal surface and encased the pectinate muscles. These findings suggest that LAA remodeling (dilation, stretching, and reduction in pectinate muscle volume, as well as endocardial fibroelastosis) occurs frequently in chronic AF and may contribute to the increased risk of thrombus formation and systemic embolism. Additionally, the information may have relevance in interpreting transesophageal echocardiographic images of the LAA in patients with chronic AF.

Lipoprotein(a), left atrial appendage function and thromboembolic risk in patients with chronic nonvalvular atrial fibrillation.

Lipoprotein(a) (Lp(a)) has a prothrombotic effect by modulating the fibrinolytic system. The purpose of the present study was to determine whether serum Lp(a) levels are associated with an increased risk of thromboembolism in chronic nonvalvular atrial fibrillation (NVAF). Clinical, laboratory and transesophageal echocardiographic data were collected in 172 consecutive, non-anticoagulated patients with chronic NVAF. Thirty-four patients (thromboembolic group) had a recent (<1 month) embolic event and/or a left atrial thrombus on transesophageal echocardiography. The thromboembolic group had a higher frequency of spontaneous echo contrast (94 vs. 58%, p<0.0001), increased concentrations of Lp(a) (median: 31.5 vs. 15.5 mg/dl, p<0.0001) and fibrinogen (median: 352 vs. 314 mg/dl, p = 0.0015), larger left atrial dimensions (median: 5.1 vs. 4.8cm, p = 0.0078), and reduced left atrial appendage (LAA) flow velocities (median: 9.5 vs. 21.2 cm/s, p<0.0001) than the nonthromboembolic group. Multivariate analysis identified 3 independent predictors of thromboembolism: Lp(a) level > or =30 mg/dl (odds ratio (OR) 9.5, 95% confidence interval (CI) 4.4-20.4, p<0.0001), LAA flow velocity of <20 cm/s (OR 8.7, 95% CI 3.3-23.0, p = 0.0003) and a fibrinogen concentration of <377mg/dl (OR 3.2, 95% CI 1.5-6.9, p = 0.0201). The Lp(a) elevations and reduced LAA flow velocities are independently associated with thromboembolism in chronic NVAF.

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

Non-valvular atrial fibrillation (AF) is associated with an increased risk of stroke. The objective of this review was to characterize the efficacy and safety of oral anticoagulation (OAC) with vitamin K antagonists for the primary prevention of stroke in patients with chronic AF. We searched the Cochrane Stroke Group Specialised Register of Trials (June 1999), MEDLINE database, and the database of the Antithrombotic Trialists Collaboration, as well as reference lists of relevant articles. All randomized controlled trials comparing the value of OAC versus control in patients with non-valvular chronic atrial fibrillation and no history of transient ischemic attack (TIA) or stroke. Trials for inclusion were independently selected by two reviewers who also extracted each outcome and double-checked the data. The Peto method was used for combining odds ratios. All analysis were, as far as possible, "intention-to-treat". Since the published results of four trials included 3-8% of participants with prior stroke or TIA, unpublished results excluding these participants were obtained from the Atrial Fibrillation Investigators. Of 2313 participants without prior cerebral ischemia from five trials, about half (n = 1154) were randomized to adjusted-dose OAC with an estimated mean INRs ranging between 2.0-2.6 during 1.5 years/participant average follow-up. Participant features and study quality were similar between trials. OAC was associated with large, highly statistically significant reductions in ischemic stroke (OR = 0.34, 95% CI 0.23 - 0.52), all stroke (OR = 0.39, 95% CI 0.26 - 0. 59), all disabling or fatal stroke (OR = 0.47, 95% CI 0.28 - 0.80), and the combined endpoint of all stroke, MI or vascular death (OR = 0.56, 95% CI 0.42 - 0.76). The observed rates of intracranial and extracranial hemorrhage not significantly increased by OAC therapy, but confidence intervals were wide. Adjusted-dose OAC (achieved INRs between 2-3) reduces stroke as well as disabling/fatal stroke for patients with nonvalvular AF, and these benefits were not substantially offset by increased bleeding among participants in randomized clinical trials. Limitations include relatively short follow-up and imprecise estimates of bleeding risks from these selected participants. For primary prevention in AF patients who have an average stroke rate of 4%/year, about 25 strokes and about 12 disabling fatal strokes would be prevented yearly for every 1000 given OAC.

Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks.

Atrial fibrillation (AF) carries an increased risk of stroke; antiplatelet agents are proven effective for stroke prevention in other settings. The objective of this review was to determine the efficacy and safety of antiplatelet therapy for prevention of stroke in patients with chronic non-valvular AF. We searched the Cochrane Stroke Group Specialised Register of Trials, MEDLINE database (June 1999), and the database of the Antithrombotic Trialists Collaboration, as well as reference lists of relevant articles. All randomized trials comparing antiplatelet therapies to placebo in patients with non-valvular AF and no history of transient ischemic attack (TIA) or stroke. Trials for inclusion were independently selected by two reviewers who also extracted each outcome and double-checked the data. The Peto method was used for combining odds ratios. All analysis were, as far as possible, "intention-to-treat". Since the published results of two trials included 3-8% of participants with prior stroke or TIA, unpublished results excluding these participants were obtained from the Atrial Fibrillation Investigators. Among 1680 participants without prior stroke/TIA, randomized to aspirin (N = 838) or placebo in two trials, aspirin was associated with nonsignificantly lower risks of ischemic stroke (OR = 0.71, CI 95% 0. 46 - 1.10), all stroke (OR = 0.70, CI 95% 0.45 - 1.08) all disabling/fatal stroke (OR =0.88, CI 95% 0.48 - 1.58) and the constellation of stroke, MI or vascular death (OR = 0.76, CI 95% 0. 54 - 1.05 ). Considering all randomized participants including those with prior stroke or TIA, reductions in these events by aspirin were consistently smaller and marginally statistically significant: ischemic stroke (OR = 0.77, CI 95% 0.60-1.00), all stroke (OR = 0.76, CI 95% 0.61 - 0.93), all disabling/fatal stroke (OR = 0.87, CI 95% 0.64 - 1.19) and the combined outcome (OR = 0.79, CI 95% 0.64 - 0. 99). No increase in major hemorrhage was seen, but the number of hemorrhagic events was small. Considering all randomized data, aspirin modestly (by about 20%) reduces stroke and major vascular events in nonvalvular AF. For primary prevention among AF patients with an average stroke rate of 4.5%/year, about 10 strokes would be prevented yearly for every 1000 given aspirin.