Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators.

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.     

Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation

We studied whether hemostatic abnormalities contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation. Hemostatic function was studied in four age-matched groups: 20 patients with nonvalvular atrial fibrillation and a previous ischemic stroke, 20 patients with nonvalvular atrial fibrillation without a previous stroke, 20 stroke patients with sinus rhythm, and 40 healthy controls. Both groups with nonvalvular atrial fibrillation had significantly higher concentrations of von Willebrand factor, factor VIII:C, fibrinogen, D-dimer (a fibrinolytic product), beta-thromboglobulin, and platelet factor 4; a significantly higher fibrinogen/antithrombin ratio; and significantly higher spontaneous amidolytic activity than the healthy controls. Prekallikrein levels were significantly lower in both groups with nonvalvular atrial fibrillation. Stroke patients with sinus rhythm had normal hemostatic function, normal concentrations of platelet-related factors, and a slightly increased concentration of fibrinopeptide A compared with the healthy controls. Both groups with nonvalvular atrial fibrillation differed from the stroke patients with sinus rhythm as they did from the healthy controls. No difference in hemostatic function was seen between the nonvalvular atrial fibrillation patients with and without a previous ischemic stroke. Thus, alterations in hemostatic function may contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation.     

Plasma levels of coagulation and fibrinolysis markers in acute ischemic stroke patients with lone atrial fibrillation

Atrial fibrillation (AF) is a well-defined risk factor for ischemic stroke. Patients with lone AF represent a subgroup of AF patients with the lowest lifelong stroke risk. Nonvalvular atrial fibrillation (NVAF) confers a hypercoagulable state resulting in an increased risk of thromboembolism. This study was performed to determine the contributory role of alteration in the hemostatic markers of thrombin generation and fibrinolysis in patients with lone AF during acute ischemic stroke episode. We studied thrombin-antithrombin complexes (TAT), prothrombin fragments 1+2 (F1+2), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) concentrations in patients with acute middle cerebral artery ischemic stroke due to atherosclerotic large artery disease (n=50), lone AF (n=24) and cardioembolism (n=21). The values were compared with those of age-matched control subjects with lone AF and sinus rhythm (n=21 and 15, respectively). The mean F1+2 concentration was higher in the control subjects with lone AF in comparison with those without AF (p=0.014). Patients with stroke due to possible cardioembolism, from lone AF or other causes, had higher TAT (and marginally higher F1+2) concentrations than those with atherosclerotic stroke (p<0.001). tPA concentrations were not different among groups (p=0.89). PAI-1 levels were marginally higher in stroke patients with lone AF and atherothrombotic large artery disease compared to the controls without AF (p=0.05). These results suggest that in the acute period of ischemic stroke secondary to lone AF, enhancement of the coagulatory activity occurs as a result of increased thrombin generation, similar to other possible sources of cardioembolism. Observed hemostatic alterations in acute ischemic stroke associated with lone AF may indicate some therapeutic and prognostic implications. Received: 3 April 2000 / Accepted in revised form: 20 September 2000     

D‐dimer levels and stroke progression in patients with acute ischemic stroke and atrial fibrillation

Krarup L‐H, Sandset EC, Sandset PM, Berge E. D‐dimer levels and stroke progression in patients with acute ischemic stroke and atrial fibrillation.
Acta Neurol Scand: 2011: 124: 40–44.
© 2010 John Wiley & Sons A/S. Background – Patients with acute ischemic stroke and atrial fibrillation are at increased risk of stroke progression and recurrence. We sought to assess whether D‐dimer and other markers of hemostatic activation could predict these adverse events in such patients. Method – Blood samples were obtained from patients included in the Heparin in Acute Embolic Stroke Trial. Stroke progression was defined as a ≥3‐point worsening on the Scandinavian Stroke Scale during the first 48 h after randomization. Blood samples were analyzed for D‐dimer, prothrombin fragment 1 + 2, soluble fibrin monomer, and C‐reactive protein. Results – A total of 382 patients were included in the analyses. Levels of D‐dimer and other markers of hemostatic activation were not significantly higher in patients with stroke progression than in other patients (D‐dimer median values: 1025 ng/ml vs 970 ng/ml, P = 0.73). The same was true for recurrent stroke (D‐dimer: 720 ng/ml vs 973 ng/ml, P = 0.96), and the combined endpoint of stroke progression, recurrent stroke, and death (D‐dimer: 991 ng/ml vs 970 ng/ml, P = 0.91). Multivariable analyses did not alter the results. Conclusion – D‐dimer and other markers of hemostatic activation were not associated with stroke progression, recurrent stroke, or death in patients with acute ischemic stroke and atrial fibrillation.     

Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation

BACKGROUND AND PURPOSE: Recent clinical trials have established that adjusted-dose warfarin (international normalized ratio [INR] 2.0 to 3.0) is highly effective in the reduction of ischemic stroke in patients with nonvalvular atrial fibrillation (AF). We hypothesized that the introduction of fixed low-dose warfarin alone or in combination with aspirin (300 mg) could normalize hemostatic markers, namely plasma fibrin D-dimer (an index of thrombogenesis), plasminogen activator inhibitor-1 (PAI-1, an index of fibrinolysis), fibrinogen, and von Willebrand factor (vWf, an index of endothelial dysfunction), in a manner comparable to adjusted-dose warfarin (target INR 2.0 to 3.0). METJODS: Sixty-one patients with AF (44 men, mean+/-SD age 64+/-19 years) who were not receiving any antithrombotic therapy were prospectively randomized into 1 of 3 treatment groups: warfarin (2 mg) (n=23; group 1), combination 1 mg warfarin plus 300 mg aspirin (n=21; group 2) or combination 2 mg warfarin plus 300 mg aspirin (n=17; group 3). Subjects from all 3 AF groups were matched for sex, age, and blood pressure. Blood samples were taken for sequential measurements for changes in plasma fibrin D-dimer, PAI-1, fibrinogen, and vWf before and at 2 and 8 weeks after randomization (phase 1). All patients were subsequently offered adjusted-dose warfarin therapy (phase 2), and an additional blood sample was taken 6 weeks later. RESULTS: When pretreatment results were compared with those from 60 age- and sex-matched healthy control subjects in sinus rhythm, there were significant elevations in levels of fibrinogen (P=0.025), vWf (P<0.0001), and fibrin D-dimer (P<0.0001) in patients with AF compared with control subjects. There were no significant changes in the levels of various indices measured after 2 and 8 weeks of therapy in all 3 groups, except for an increase in PAI-1 level (P=0.024) in group 3. After 6 weeks of therapy with dose-adjusted warfarin (INR 2.0 to 3.0), there was a significant decrease in plasma fibrinogen (P=0.023) and fibrin D-dimer (P=0.0067) levels. There were no significant changes in the levels of PAI-1 (P=0.198) or vWf (P=0.33). CONCLUSIONS: The present results confirmed that high levels of vWf, fibrinogen, and fibrin D-dimer levels were present in patients with AF compared with control subjects. Moreover, the introduction of 300 mg aspirin plus low-dose warfarin (1 mg/d), low-dose warfarin alone (2 mg/d), or 300 mg aspirin plus low-dose warfarin (2 mg/d) did not significantly reduce any of the hemostatic markers studied (except PAI-1 levels), whereas conventional full-dose warfarin (INR 2.0 to 3.0) significantly reduced levels of fibrin D-dimer and fibrinogen. These results are in keeping with the disappointing ineffectiveness of low-intensity warfarin therapy, aspirin-warfarin combination, and ultralow-dose warfarin therapy in the recent prematurely terminated clinical trials and the established benefits of conventional adjusted-dose anticoagulation therapy.     

In-hospital onset ischemic stroke may be associated with atrial fibrillation and right-to-left shunt

BACKGROUND AND PURPOSE: Ischemic stroke during hospitalization can occasionally be found, but the mechanisms and causes underlying stroke have not been investigated in detail. The present study aimed to identify differences in stroke etiology between in-hospital and out-of-hospital onset. METHODS: Subjects comprised 357 consecutive patients (221 men, 136 women) with ischemic stroke prospectively enrolled within 24 h of onset. Contrast saline transcranial Doppler ultrasonography (c-TCD) or transesophageal echocardiography (TEE) was performed in all participants to identify right-to-left shunts (RLS). Patients were divided into 2 groups: in-hospital onset (IHO group, n=49); and out-of-hospital onset (OHO group, n=308). Clinical characteristics were compared between groups. RESULTS: Mean age was 71.5+/-12.3 years. Mean National Institute of Health stroke scale score was 6.9+/-7.2. RLS, atrial fibrillation (AF) and malignancy were more frequent in the IHO group than in the OHO group (39% vs. 20%, p=0.006; 45% vs. 16%, p<0.001; 18% vs. 4%, p<0.001, respectively). AF and/or RLS was more frequent in the IHO group (61%) than in the OHO group (30%, p<0.001). CONCLUSION: Ischemic stroke with in-hospital onset may be associated with AF and RLS.     

Atherothrombotic ischemic stroke in patients with atrial fibrillation

OBJECTIVES: About one in five patients with atrial fibrillation have significant carotid artery disease, but not all strokes are cardioembolic in origin in these patients. PURPOSE: We investigated stroke sub-types based mainly on clinical, carotid ultrasonographic, and neuroimaging findings in ischemic stroke patients with non-valvular atrial fibrillation (NVAF). PATIENTS AND METHODS: The etiology of stroke was classified as definite or probable cardioembolic, possible lacunar, or possible atherothrombotic, as proposed by Hart et al. and the TOAST criteria. Clinical features and risk factors (gender, age, diabetes mellitus, hypertension, hyperlipidemia, cigarette smoking, and alcohol consumption) were designated as clinical variables. RESULTS: One hundred and six of 1938 patients (5.5%) had NVAF. In patients with and without NVAF, hyperlipidemia was more common in patients without NVAF (p<0.001), while the prevalence of other risk factors was not statistically different. On the basis of the TOAST criteria, none of the patients with NVAF could be classified as having had an atherothrombotic stroke. According to the classification by Hart et al., of the patients with NVAF, 49 patients (46.3%) had a definite embolic stroke, 17 (16.0%) had a probable embolic stroke, 12 (11.3%) had a possible atherothrombotic stroke, 17 (16.0%) had a possible lacunar infarction, and 11 (10.4%) had a stroke of undetermined etiology. Besides the presence of significant carotid stenosis (p<0.001), none of the variables related to stroke were different among the sub-groups. CONCLUSION: Patients with significant carotid stenosis were more likely to develop atherothrombotic stroke, while other risk factors associated with stroke failed to point to an etiologic cause. It should also be emphasized that the conventional classification system failed to aid in the correct diagnosis and risk stratification in patients with multiple confounding risk factors.     

Warfarin for stroke prevention still underused in atrial fibrillation: patterns of omission

BACKGROUND AND PURPOSE: The value of warfarin in preventing stroke in patients with chronic atrial fibrillation is well established. However, the prevalence of such treatment generally lags behind actual requirements. The aim of this study was to evaluate doctor- and/or patient-related demographic, clinical, and echocardiographic factors that influence decision for warfarin treatment. METHODS: Between 1990 and 1998, 1027 patients were discharged with chronic or persistent atrial fibrillation. This population was composed of (1) patients with cardiac prosthetic valves (n=48), (2) those with increased bleeding risks (n=152), (3) physically or mentally handicapped patients (n=317), and (4) the remaining 510 patients, the main study group who were subjected to thorough statistical analysis for determining factors influencing warfarin use. RESULTS: The respective rates of warfarin use on discharge in the 4 groups were 93.7%, 30.9%, 17.03%, and 59.4% (P=0.001); of the latter, an additional 28.7% were discharged on aspirin. In the main study group, warfarin treatment rates increased with each consecutive triennial period (29.7%, 53.6%, and 77.1%, respectively; P=0.001). Age >80 years, poor command of Hebrew, and being hospitalized in a given medical department emerged as independent variables negatively influencing warfarin use: P=0.0001, OR 0.30 (95% CI 0.17 to 0.55); P=0.02, OR 0.59 (95% CI 0.36 to 0.94); and P=0.0002, OR 0.26 (95% CI 0.12 to 0.52), respectively. In contrast, past history of stroke and availability of echocardiographic information, regardless of the findings, each increased warfarin use (P=0.03, OR 1.95 [95% CI 1.04 to 3.68], and P=0.0001, OR 3.52 [95% CI 2.16 to 5.72], respectively). CONCLUSIONS: Old age, language difficulties, insufficient doctor alertness to warfarin benefit, and patient disability produced reluctance to treat. Warfarin use still lags behind requirements.     

Interventional treatments for stroke prevention in atrial fibrillation with emphasis upon the WATCHMAN device

PURPOSE OF REVIEW: Stroke is a leading cause of death and disability worldwide. Many strokes occur in patients with atrial fibrillation. Current guidelines recommend an antithrombotic regimen with warfarin to prevent thromboembolism in atrial fibrillation; however, a substantial number of patients are not eligible for this therapy. The exclusion of the left atrial appendage from circulation seems to be an alternative strategy for stroke prevention in atrial fibrillation. The review focuses on the different devices for stroke prevention in patients with atrial fibrillation. RECENT FINDINGS: Recently, two devices developed for percutaneous transcatheter occlusion of the left atrial appendage have been studied: the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) device and the WATCHMAN device. Safety and feasibility data are available for both devices. About 200 patients have received a PLAATO device. These patients were at high risk for thrombembolic stroke and were not candidates for oral anticoagulation therapy. The WATCHMAN device was implanted in 75 patients that were eligible for long-term anticoagulation therapy with a moderate risk for thrombembolic stroke due to nonvalvular atrial fibrillation. SUMMARY: For both devices, a reduction in the risk of stroke was documented, and device implantation was shown to be safe and feasible. Provided the ongoing trials show noninferiority to oral anticoagulation, another therapeutic option will become available to prevent ischemic strokes.     

Mortality in acute stroke with atrial fibrillation. The Italian Acute Stroke Study Group

We compared 211 consecutive patients who had acute ischemic hemispheric stroke and atrial fibrillation with 837 consecutive patients who had stroke without atrial fibrillation. The atrial fibrillation group included a higher frequency of women, older subjects, and those with a severe neurologic deficit, abnormal computed tomogram, and elevated heart rate. The 1-month case-fatality rate in the atrial fibrillation group was 27% while that in the group without atrial fibrillation was 14%. The 6-month case-fatality rates in the two groups were 40% and 20%, respectively. The risk of death attributable to atrial fibrillation, adjusted for the effect of other prognostic factors, was significant at 1 month (relative risk = 1.55) and at 6 months (relative risk = 1.74). The causes of death were equally distributed in the two groups during both the acute and subacute phases. We conclude that atrial fibrillation is a negative prognostic factor in patients hospitalized for acute stroke. Nevertheless, cerebral embolism alone does not completely explain the increase in mortality for stroke patients with atrial fibrillation. Other associated pathogenetic mechanisms must also be taken into account.     

A prospective study of atrial fibrillation and stroke

In a prospective study of 72 patients with stroke and atrial fibrillation, we classified strokes as cardioembolic or noncardioembolic based on arterial assessment using Doppler sonography and angiography. We analyzed and cross-tabulated 18 clinical characteristics and found four to be significantly associated with a cardioembolic mechanism: stroke with onset during activity and peak deficit at onset (p less than 0.008), previous infarct in a different vascular territory (p less than 0.01), previous transient ischemic attack in a different vascular territory (p less than 0.01), and transient ischemic attack lasting greater than 1 hour (p less than 0.02). Starting with these four characteristics, we used a step-down procedure to select variables for a logistic regression model. Only previous infarct in a different vascular territory (odds ratio = 7.38) and transient ischemic attack lasting greater than 1 hour (odds ratio = 7.89) were selected by the model. Using M-mode and two-dimensional echocardiography, we compared left atrial size in 46 patients with that in 78 controls who had atrial fibrillation without stroke. Left atrial size in patients and controls with mitral valvulopathy was significantly larger than that in patients and controls without mitral valve disease. There was, however, no difference in left atrial size between patients with nonvalvular atrial fibrillation and cardioembolic stroke and controls or patients with nonvalvular atrial fibrillation and noncardioembolic stroke. We concluded that some clinical characteristics are closely related to cardioembolic stroke and that left atrial enlargement reflects underlying cardiopathy rather than atrial emboli-forming capability.     

Impact of comorbidity on ischemic stroke outcome

OBJECTIVE: To evaluate the impact of comorbidity on stroke outcome of patients admitted to a general ward (GW) and a stroke unit (SU). METHODS: Data of 266 patients with acute ischemic stroke (GW: 103, SU: 163) were collected prospectively for 13 months. Clinical and radiological findings, and the Charlson Comorbidity Index (CCI) were recorded. Predictors of outcome 4 months after stroke were analyzed. Favorable outcome was defined as modified Rankin Scale (mRS) score of < or = 2, unfavorable as mRS >2. RESULTS: The mean age of the patients was 67.2 years (SD = 14.4), the mean CCI 1.2 (SD = 1.4). In univariate analysis, small artery disease predicted favorable outcome (P < 0.001) and age (P = 0.022), high National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001), high CCI (P < 0.001), treatment in a GW (P = 0.004), coronary artery disease (P = 0.02), dementia (P = 0.009), diabetes (P = 0.005) and atrial fibrillation (P < 0.001) unfavorable outcome after 4 months. In multivariate analysis, high NIHSS score (P < 0.001), atrial fibrillation (P = 0.004), coronary artery disease (P = 0.012) and diabetes (P = 0.031) were predictors of unfavorable outcome. CONCLUSIONS: Comorbidity has a significant impact on stroke outcome. In addition to stroke severity, atrial fibrillation, coronary artery disease and diabetes were predictors of outcome after stroke, but not the sum of the CCI.     

Stroke in thyrotoxicosis with atrial fibrillation

Chronic atrial fibrillation is associated with an increased risk of stroke. In elderly patients with thyrotoxicosis, atrial fibrillation is frequently encountered, and the true risk of cerebrovascular events in these patients is controversial. We retrospectively studied 610 patients with initially untreated thyrotoxicosis, 91 (14.9%) of whom had atrial fibrillation, with the highest frequency in the elderly patients. The risk of cerebrovascular events, with special attention to the first year after the diagnosis of thyrotoxicosis, was calculated using logistic regression methods with age, sex, and atrial fibrillation as independent variables. Only age was an important risk factor (p less than 0.005), whereas sex and atrial fibrillation were not significant (p = 0.09 and p = 0.17, respectively) as independent risk factors. This is contrary to other studies of patients with thyrotoxic atrial fibrillation, and the need for further clarification of this issue is clear. From our study the indication for prophylactic treatment with anticoagulants for prevention of stroke in thyrotoxic atrial fibrillation seems doubtful, especially as no controlled studies of such treatment in patients with atrial fibrillation are currently available.     

Rationale for antithrombotic therapy in atrial fibrillation.

Antithrombotic therapy is clearly indicated in patients with atrial fibrillation who have associated factors that put them at significant risk for thromboembolism This does not include subjects with lone atrial fibrillation who are less than 60 years of age. High-risk patients include those with valvular heart disease, recent congestive heart failure, severe left ventricular dysfunction by echocardiography, prior thromboembolism, demonstration of a cardiac thrombus by echocardiography, and thyrotoxicosis. Anticoagulant therapy appears to be the most efficacious means of preventing thromboembolism in atrial fibrillation. Potential bleeding complications with sodium warfarin mandate judicious selection of patients for long-term anticoagulant therapy. The risk of anticoagulant therapy certainly appears justified in subjects who are at high risk for thromboembolism and can be monitored with a reasonable degree of safety. Aspirin therapy is a reasonable alternative for those subjects at relatively lower risk of thromboembolism, especially subjects who are not suitable candidates for anticoagulation. The efficacy of aspirin has not been established in patients with atrial fibrillation who are greater than 75 years of age.     

Pulmonary hypertension: An unexplored risk factor for stroke in patients with atrial fibrillation

BackgroundAtrial fibrillation (Afib) is one of the most common and significant risk factors for stroke, with the CHADsVAsc score used as the tool for stroke risk assessment. Pulmonary hypertension (PH) has not been studied as an independent risk factor for stroke in individuals with Afib.MethodsIn this retrospective case-control study, National Inpatient Sample Database was used to sample individuals with atrial fibrillation, and baseline demographics and comorbidities were collected using ICD-10 codes. Patients with missing data, age under 18, history of thromboembolic diseases, or stroke were excluded. Greedy propensity matching using R was performed to match patients with and without PH on age, race, gender, and 19 other comorbidities, including anticoagulation use. Binary logistic regression was performed after matching to assess whether PH was an independent risk factor for stroke. A p-value of <0.05 was considered statistically significant.ResultsOf the 2,421,545 patients included in the study, 158,545 (6.5%) had PH. PH patients were more likely to be elderly, females, and smokers. Comorbidities were more common in the PH group. Patients with PH were more likely to have an ischemic stroke (3.6% vs. 2.9%, p<0.001), hemorrhagic stroke (2.2% vs. 0.7%, p<0.001), and transient ischemic attack (TIA) (2.3% vs. 0.7%, p<0.001). After matching, the presence of PH was associated with increased ischemic stroke (OR: 1.2 [1.1-1.2]; p<0.001), hemorrhagic stroke (OR: 2.4 [2.1-2.6]; p<0.001) and TIA (OR: 2.2 [2.0-2.4]; p<0.001). PH patients also had increased length of stay (β = 0.8; p<0.001) mortality (OR: 1.1 [1.0-1.2]; p<0.001).ConclusionApart from demonstrating the deleterious effect of PH on mortality and length of hospital stay, this study is the first to report on such a large scale that PH independently increases the incidence of all types of strokes in patients with Afib.     

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

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

Cardioembolic vs. noncardioembolic strokes in atrial fibrillation: frequency and effect of antithrombotic agents in the stroke prevention in atrial fibrillation studies

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.     

Clinical and echocardiographic measures governing thromboembolism destination in atrial fibrillation

Although infrequent, embolic occlusion to non-cerebral arteries may result in limb loss, organ failure, and death. The aim of this study was to define clinical and echocardiographic characteristics determining thromboembolism destination in non-valvular atrial fibrillation. An inception cohort of individuals (n=72) were identified with incident peripheral embolism in the setting of non-valvular atrial fibrillation (1995-2005). A randomly selected group of atrial fibrillation related stroke patients (n=100) were identified for comparison. Arteries of the extremities were the most common site of embolism (85%); lower extremity involvement was twice as common compared with the upper extremity. Clinical features distinguishing peripheral embolism from stroke included age>75, heart failure and hypertension. Severe left ventricular dysfunction, spontaneous echo contrast and left atrial thrombus were 2-3 fold more common in peripheral embolism patients. Mean CHADS-2 scores were low and comparable for both groups. By multivariate analysis, age>5 years (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.3-3.9; p=0.05) was predictive of peripheral embolism. After adjustment for age>75 years, severe left atrial enlargement (HR 1.8, 95% CI 0.99-3.1; p=0.055) and CHADS score (HR 1.2, 95% CI 0.99-1.6; p=0.06) were of borderline significance. In conclusion, several clinical and echocardiographic measures distinguish the clinical presentation of thromboembolism in non-valvular atrial fibrillation. Small emboli are destined to lodge in the cerebral circulation as a result of hydrodynamic, anatomic, and physical factors. Advanced age, atrial enlargement and other co-morbidities may increase the propensity for the formation of larger thrombi which may bypass the carotid orifice merely as a function of size.     

Atrial fibrillation after stroke in the elderly

To examine the relationship between atrial fibrillation and mortality after stroke, we studied 186 men and 167 women from the Waikato Stroke Registry whose mean age was 75.2 +/- 7.5 years. Twenty-three percent (82 of 353) had atrial fibrillation or flutter on their admission electrocardiogram. This group differed significantly from that with sinus rhythm in three respects: 1) They were older (p less than 0.01); 2) they had more severe current stroke deficit as evidenced by lower limb power (p less than 0.05) and Mini-Mental State Score (p less than 0.001), higher incidence of homonomous hemianopia (p less than 0.05), and lower incidence of lacunar syndrome stroke (p less than 0.001); and 3) they had a significantly higher incidence of cardiomegaly and congestive heart failure (p less than 0.01). Functional outcome was insignificantly better in the group with sinus rhythm. During a mean follow-up period of 18 months, mortality was significantly higher in the group with atrial fibrillation (p = 0.001). Proportional hazards modeling, however, showed that the apparently poorer survival in those patients with atrial fibrillation could be explained by factors other than cardiac rhythm, such as age, Mini-Mental State Score, level of consciousness, and interstitial edema on admission chest radiograph. Thus, atrial fibrillation was not an independent predictor of survival after stroke.     

Primary prevention of thrombosis for patients with atrial fibrillation]

Clinical importance of antithrombotic prophylaxis strategy for patients with atrial fibrillation has been focused because of the high prevalence of severe cerebral embolism especially in elderly patients. Several multicenter, randomized clinical trials for prevention of thromboemblolism performed in the Western countries have revealed efficacy of the anticoagulation therapy with warfarin over the anti-platelet aggregation therapy with aspirin. Therapeutic guideline for thromboembolism in patients with atrial fibrillation has been established based on these observations. However, special attentions should be paid for applying the guideline for Japanese patients since bleeding risk in antithrombotic treatment seems to be high in Japanese. Recently, therapeutic guideline for thromboembolism in Japanese patients with atrial fibrillation has been established. In this guideline, treatment with warfarin is also recommended for patients with atrial fibrillation. However treatment target of warfarin, ie, PT-INR, is designated rather low in Japanese patients, especially in eldely patients over 75 years old. Usage of antiplatelet treatment with aspirin is also described in this guideline for Japanese, however, the evidence suggesting the usefulness for prophylaxis with aspirin is not sufficiently obtained in Japanese patients. Further clinical studies for antithrombotic treatment are needed for Japanese patients with atrial fibrillation.