Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study.

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.

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.

Clinically significant differences in the International Normalized Ratio measured with reagents of different sensitivities. SPAF Investigators. Stroke Prevention in Atrial Fibrillation.

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.

Stroke risk in an elderly population with atrial fibrillation.

Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke, but the absolute rate of stroke varies widely depending on coexistent vascular disease. We assessed the stroke rate and predictive value of two published schemes for stroke risk stratification in a population-derived cohort of 259 elderly people with nonvalvular AF followed for a median of 5.3 years. The rate of ischemic stroke was 2.8% per year (95% confidence interval [CI] 1.9, 3.9). Thirty-one percent were predicted to be at low risk, and their stroke rate was 1.7% per year (95% CI 0.6, 3.8). Many people with AF in this population-derived cohort had relatively low rates of stroke. Further studies to reliably stratify stroke risk in patients with AF are needed.

Anticoagulation for prevention of stroke.

One of the important recent advances in stroke prevention is the demonstration that warfarin can substantially reduce the risk for stroke in patients with atrial fibrillation (AF). On average, patients with AF have a stroke risk of 4.5% per year. Anticoagulation reduces this to around 1.5% per year, a 70% relative risk reduction. The presence of additional risk factors, such as a recent stroke or transient ischemic attack, hypertension (particularly systolic hypertension), congestive heart failure, or diabetes, greatly increases stroke risk. Patients with any of these risk factors have a stroke risk of 8% per year or more. In contrast, patients under age 75 with none of these risk factors have a low risk for stroke (around 1% per year) when treated with aspirin. This risk stratification may help in identifying which patients with AF benefit most from anticoagulation. Anticoagulation has also been shown to prevent stroke in patients with other cardioembolic sources, including acute anterior wall myocardial infarction (particularly with echocardiographic evidence of thrombus), prosthetic heart valves, and dilated cardiomyopathies.

Behavioral issues in the efficacy versus effectiveness of pharmacologic agents in the prevention of cardiovascular disease.

A number of pharmacologic interventions are now recommended for the prevention of cardiovascular disease, based on the results of randomized controlled trials. These include antihypertensive drugs, lipid-lowering agents, antiplatelet and anticoagulant drugs, estrogen replacement therapy, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors. It is likely that additional pharmacologic interactions will soon be proven efficacious. Despite the strength of this evidence and the development of clinical guidelines incorporating their use, a surprisingly low proportion of patients are actively treated with these agents. There may be a variety of explanations for this, including barriers at the level of the patient, health care provider, and health care institution. Finally, a number of questions remain as to the optimal combination of interventions, both behavioral and pharmacologic, which will yield maximal reduction in risk. The description of factors which reduce the effectiveness of pharmacologic interventions below the efficacy demonstrated in randomized clinical trials should be a fertile area for epidemiologic and behavioral research.

Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

BACKGROUND AND PURPOSE: The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation. METHODS: We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P < or = .0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2 = -0.1 + 2.3[1/INR]; R2 = .37; P < .0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P < .001) in the model. There was no difference in the relationship between F1.2 and INR between men and women. CONCLUSIONS: Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.

Status of lipids as a risk factor for stroke.

There is mounting epidemiologic evidence to support the relationship of lipids as a risk factor for ischemic stroke. We review epidemiologic and pathophysiologic evidence for such a link. Treatment of hyperlipidemia is addressed within the context of overall cardiovascular disease risk but also for stroke prevention.

Hemostatic markers in acute ischemic stroke. Association with stroke type, severity, and outcome.

BACKGROUND AND PURPOSE: Hemostatic markers can identify activation of the coagulation system in stroke patients. We evaluated whether the levels of these markers at the time of stroke are correlated with stroke severity, type, or mortality. METHODS: We measured fibrinopeptide A, cross-linked D-dimer, and beta-thromboglobulin in 70 patients within 1 week of stroke. We examined the association between the level of each of these markers and survival. We adjusted for the possible confounding effect of age, stroke type, or stroke severity using a multivariate Cox proportional hazards model. RESULTS: The median follow-up was 1.22 years. Fourteen patients died during follow-up. Univariate survival analysis identified age (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12), stroke type (hazard ratio, 4.44; 95% CI, 1.29 to 15.23), initial Toronto Stroke Scale score (hazard ratio, 5.05; 95% CI, 2.08 to 12.27), cross-linked D-dimer (hazard ratio, 6.43; 95% CI, 2.83 to 14.62), fibrinopeptide A (hazard ratio, 2.14; 95% CI, 1.26 to 3.63), and beta-thromboglobulin (hazard ratio, 7.63; 95% CI, 2.22 to 26.28) as significantly associated with mortality. In a multivariate model, initial stroke severity and each of the hemostatic markers were independently associated with subsequent mortality. CONCLUSIONS: Elevated hemostatic markers after acute ischemic stroke identify patients with increased risk for mortality. This association appears to be independent of stroke severity or stroke type.

Comparison of centralized versus "site-based" measurement of angiographic stenosis for eligibility in the asymptomatic carotid atherosclerosis study.

RATIONALE AND OBJECTIVES: The authors determine the reliability of centralized versus noncentralized (site-based) measurement of angiographic stenosis of patients enrolled into the multicenter, prospective, Asymptomatic Carotid Atherosclerosis Study by angiographic studies. METHODS: Percent agreements and correlations of 244 masked and prospectively interpreted angiograms were calculated for comparison of centralized and noncentralized readers measuring the percent carotid stenosis from the same angiographic studies. Univariate summary statistics for differences in percent stenoses were calculated for these readings. RESULTS: Agreement between readings were 88.5% and 91.8% with kappa statistics of 0.77 and 0.73 for > or = 60% and > or = 80% stenosis, respectively, for comparison of 33 centers to the designated central reader. Comparison between the designated central reader and a second central reader derived percent agreements of 85.0% and 86.5% with kappa statistics of 0.69 and 0.41 for > or = 60% and > or = 80% stenoses, respectively, for arteries selected from the original group. Hence, agreement was slightly better between the enrolling centers and the designated central reader than between the two central readers. CONCLUSIONS: Both centralized and noncentralized (site-based) methods of angiographic measurement of stenosis are equally reliable for large, prospective, masked, multicenter trials when quality control measures are instituted to ensure uniform application of eligibility criteria.

The relative contributions of carotid duplex scanning, magnetic resonance angiography, and cerebral arteriography to clinical decisionmaking: a prospective study in patients with carotid occlusive disease.

PURPOSE: Recent reports suggest that 80% to 90% of patients can safely undergo carotid endarterectomy on the basis of duplex scanning alone without cerebral angiography. Other investigators have recommended that a complementary imaging study such as magnetic resonance angiography (MRA) also be obtained. METHODS: We prospectively evaluated 103 consecutive patients with carotid occlusive disease. Eighty percent of patients were symptomatic. All 103 patients underwent duplex scanning and arteriography. Additional noninvasive tests included computed tomography, magnetic resonance imaging, and MRA in 50%, 56%, and 48% of patients, respectively. At a multispecialty conference all studies except angiograms were reviewed, and a treatment decision was made by a panel of attending vascular surgeons, neurosurgeons, and neurologists. The cerebral angiograms then were reviewed and changes made to final treatment plans were noted. RESULTS: After review of noninvasive studies, 30 of 103 of patients (29%) were believed to require arteriography because of diagnostic uncertainty of carotid occlusion in three patients, suggestion of nonatherosclerotic disease in four, suggestion of proximal disease in two, suboptimal noninvasive studies in one, and uncertainty of therapy despite good-quality noninvasive studies in 20 patients primarily with borderline stenoses and unclear symptoms. In 10 of these 30 patients (33%) management decisions were changed on the basis of angiogram results. Of the remaining 73 patients (71%) in whom the panel felt comfortable proceeding with operative or medical therapy without angiography, only one patient (1.4%) would have had management altered by results of angiography. MRA results concurred with duplex findings in 92% of studies, but did not alter management in any patient. CONCLUSIONS: In patients with good-quality duplex images, focal atherosclerotic bifurcation disease, and clear clinical presentation, treatment decisions can be made without arteriography. In 30% of patients angiography is useful in clarifying decisionmaking. MRA is unlikely to influence management decisions and is thus rarely indicated.

Primary and secondary stroke prevention.

Recent clinical trials have demonstrated that we can prevent stroke with appropriate medical and surgical therapy. Treatment of stroke risk factors, antiplatelet therapy, anticoagulant therapy, and carotid endarterectomy have all proven to be effective if applied in appropriate clinical circumstances. This review will highlight the areas in which we have clinical trial evidence to guide us, and will point out those circumstances in which uncertainty remains.

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

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