Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. OBJECTIVES: To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. METHODS: HAS-BLED, ORBIT, ATRIA and HEMORR2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. RESULTS: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P < 0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P = 0.0019), ATRIA (P < 0.001) and HEMORR2 HAGES (P < 0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P = 0.0607). CONCLUSIONS: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

Basic fibroblast growth factor increases tissue factor expression in circulating monocytes and in vascular wall.

BACKGROUND: Basic fibroblast growth factor (bFGF) promotes vascular repair and angiogenesis and can induce in vitro tissue factor (TF), a potent agent initiating thrombogenesis, which probably plays a role in angiogenesis. We investigated whether bFGF administration induced TF expression by monocytes and vascular cells. METHODS AND RESULTS: We studied TF expression in normally fed (n=16) and cholesterol-fed (2% for 6 weeks, n=16) rabbits. Animals were then randomized to receive intravenous bFGF (2.5 microg twice weekly for 3 weeks) or saline injections. TF expression was evaluated in mononuclear cells from arterial blood and in aortic sections by an immunohistochemical assay using a monoclonal anti-rabbit TF antibody (activator protein 1). Monocyte TF expression was increased by bFGF administration in both normal and hypercholesterolemic rabbits (129+/-45 versus 19+/-3 mU TF/1000 monocytes, P<0.05, and 31+/-12 versus 7+/-1 mU TF/1000 monocytes, P<0.005, respectively) and was further increased by stimulation of monocytes by endotoxin in vitro. TF expression was lower in hypercholesterolemic rabbits than in normal rabbits. In the media of the vascular wall, bFGF induced strong TF expression in normal rabbits and only weak TF expression in hypercholesterolemic ones. CONCLUSIONS: This study demonstrates that systemic administration of bFGF induces an impressive increase of TF expression in circulating monocytes and in the vascular wall in normal and to a lower extent in hypercholesterolemic rabbits. The significance of this observation in terms of inducing thrombosis in vivo needs clarification.

Effect of lovastatin on intimal hyperplasia after balloon angioplasty: a study in an atherosclerotic hypercholesterolemic rabbit.

Restenosis, the major limitation of balloon angioplasty, is the result of intimal hyperplasia after the procedure. Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) inhibitor, may influence intimal hyperplasia by lowering serum cholesterol and by blocking deoxyribonucleic acid (DNA) synthesis. To determine whether lovastatin reduces intimal hyperplasia, a prospective, randomized blinded study was performed in 60 atherosclerotic New Zealand White male rabbits. Atherosclerosis was produced by air desiccation injury followed by a 28 day diet of 2% cholesterol and 6% peanut oil that was terminated before balloon angioplasty was performed. Angioplasty could not be performed in 14 rabbits with bilateral femoral artery occlusion, and in one rabbit the procedure was a technical failure. Forty-five rabbits underwent balloon angioplasty performed with use of a 2.5-mm balloon inflated to 10 atm for three 1 min dilations at 1 min intervals. Seven rabbits died during the procedure. Thirty-eight rabbits were randomized to either a lovastatin group (6 mg/kg body weight per day) or a control group. Angioplasty was performed on all patent vessels (n = 54); the procedure was bilateral in 16 rabbits and unilateral in 22. Fifteen lovastatin-treated and 15 control rabbits survived 39 days after angioplasty and were then killed. Angiograms, obtained before and 10 min and 39 days after balloon angioplasty, were read with use of electronic calipers by two observers who had no knowledge of treatment data. After the rabbits were killed, vessels were pressure perfused using a standardized protocol to maintain in vivo dimensions for blinded quantitative histologic analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro evaluation of c7E3-Fab (ReoPro) eluting polymer-coated coronary stents.

OBJECTIVE: Stent thrombosis and in-stent restenosis remain problematic in certain patient sub-groups. c7E3-Fab (ReoPro, abciximab) inhibits the platelet glycoprotein IIb/IIIa receptor as well as the smooth muscle cell alpha(v)beta3 receptor, and thus may influence both processes, especially if high local concentrations could be achieved. We have studied the adsorption and elution characteristics of c7E3-Fab on commercially available polymer-coated stents. We have also investigated the effect of such antibody binding on platelet deposition in vitro, and on antibody deposition into ex vivo human saphenous vein wall to assess whether such stents may influence stent thrombosis and restenosis. METHODS AND RESULTS: Adsorption was measured using a radioisotope technique after immersing segments of polymer-coated stents in c7E3-Fab solutions. Uptake was dependent on antibody concentration and duration of immersion of wire in the solution. After 22 h (at 5 mg ml(-1)), 1146+/-101 ng cm(-1) wire was adsorbed. In an in vitro perfusion circuit, the antibody eluted slowly, with 53% remaining after 12 days washing. To determine the value that such stents might have in clinical practise, adsorption to balloon-mounted stents was assessed at room temperature, using commercially available c7E3-Fab (2 mg ml(-1)). Efficacy of eluting c7E3-Fab was determined by measuring deposition of 111-Indium platelets. Immersing stents in c7E3-Fab for 20 min inhibited platelet deposition by 82.3% compared to controls (P=0.018). Deployment of treated stents in ex vivo saphenous vein resulted in the deposition of c7E3-Fab in the intima and media. CONCLUSIONS: c7E3-Fab can be passively adsorbed onto polymer-coated stents. It elutes slowly and in a predictable manner, significantly inhibiting platelet deposition in vitro. These studies pave the way to developing stent-based delivery of a potent anti-platelet agent that may additionally affect smooth muscle cell activity.

Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Anemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). OBJECTIVES: To investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. PATIENTS AND METHODS: We retrospectively analyzed the RE-LY trial database, which randomized 18 113 patients with AF and a risk of stroke to receive dabigatran or warfarin for a median follow-up of 2 years. Cox regression analysis was used to determine whether anemia predicted cardiovascular events and bleeding complications in these patients. RESULTS: Anemia was present in 12% of the population at baseline, and the presence of anemia was associated with a higher risk of thromboembolic cardiovascular events, including the composite endpoint of all-cause mortality or myocardial infarction (adjusted hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.32-1.71) and the primary RE-LY outcome of stroke or systemic embolism (adjusted HR 1.41, 95% CI 1.12-1.78). Anemia was also associated with a higher risk of major bleeding complications (adjusted HR 2.14, 95% CI 1.87-2.46) and discontinuation of anticoagulants (adjusted HR 1.40, 95% CI 1.28-1.79). The association between anemia and outcome was similar irrespective of cardiovascular comorbidities, randomized treatment allocation, or prior use of warfarin. The incidence of events was lower in patients with transient anemia than in patients in whom anemia was sustained (adjusted HR 0.66, 95% CI 0.49-0.91). CONCLUSIONS: Anemia is associated with an increased risk of thromboembolic events, bleeding complications and mortality in anticoagulated patients with AF. These findings suggest that patients with anemia should be monitored closely during all types of anticoagulant treatment.

Demonstration of superior sagittal sinus thrombosis by indium-111 platelet scintigraphy.

Superior sagittal sinus thrombosis, documented by cerebral angiography, was demonstrated by indium-111 platelet scintigraphy in a 40-year-old man presenting with seizures and intracerebral hematoma. Early scintigraphy demonstrated focal increased indium-111 activity at the two ends of the thrombus, while later scintigraphy showed diffuse increased activity in the area of the sinus. This initial experience suggests that platelet scintigraphy may provide unique information regarding the natural history of intracranial venous thrombosis.

Human platelets labeled with In-111 8-hydroxyquinoline: kinetics, distribution, and estimates of radiation dose.

Platelets from nine normal male subjects were labeled with In-111 8-hydroxyquinoline (In-111 oxine) in the presence of plasma in either "closed" blood transfer packs or in "open" test tubes. The mean labeling efficiencies in these two systems were 27 and 53%, respectively. Mean survival time of In-111-labeled autologous platelets was 8.76 days, with a standard deviation of 1.05 according to the maximum-likelihood estimate of the gamma-function model. The initial recovery of In-111 platelets in the circulation was 57% with a standard deviation of 11%. The distribution of In-111 platelets in liver and spleen was quantitated by anterior, posterior, and transmission gamma-camera imaging. During the first 30 min, 38% of the injected dose accumulated in the spleen, 13% in the liver. No significant increase in In-111 radioactivity was observed in either of the two organs over a 3-9-day period. The bone marrow was an additional site of In-111 accumulation. The spleen was the critical organ with respect to radiation dose. The splenic dose was estimated to be 34 rad/mCi In-111 platelets, that of the liver 2.1 rad/mCi. With the injection of 100-150 microCi of In-111-labeled platelets in normal subjects, giving a splenic radiation of 5 rad, a complete 10-day survival study can be performed and uptake of In-111 in different organs can be measured quantitatively for at least 3-4 days.

Molecular cloning, characterization and expression of cDNA for rabbit brain tissue factor.

Tissue factor (TF) is a membrane anchored glycoprotein that initiates blood coagulation by forming a complex with circulating factor VII or VIIa. TF has been identified in atherosclerotic plaques and may possibly trigger thrombosis after spontaneous plaque rupture as seen in acute myocardial infarction or angioplasty. We have previously developed an atherosclerotic rabbit model for study of the acute and chronic outcomes following angioplasty. As a first step in developing inhibitors of TF, we have isolated and characterized a rabbit cDNA coding for the mature TF. The sequence comparison of rabbit TF cDNA with those of human and mouse TFs show considerable similarity at both the nucleotide and amino acid levels. The TF cDNA when expressed in E. coli demonstrates a procoagulant activity comparable to that of native rabbit brain TF. The TF activity can be blocked by a polyclonal antibody against rabbit TF.

Aurintricarboxylic acid reduces platelet deposition in stenosed and endothelially injured rabbit carotid arteries more effectively than other antiplatelet interventions.

In the present study we tested the effects of different antithrombotic interventions on platelet deposition in experimentally-stenotic rabbit carotid arteries with endothelial injury. Platelet deposition, quantitated by labeling autologous platelets with 111In-oxine, was significantly reduced compared to control animals by all interventions tested, i.e., R 68070, a drug with thromboxane A2 synthase and receptor blocking properties, BN 52021, a PAF receptor antagonist, aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (Gp) Ib/von Willebrand factor (vWf) interaction, AZ-1, a monoclonal antibody against rabbit GP IIb/IIIa, the platelet receptor for fibrinogen, and AP-1, a monoclonal antibody against rabbit tissue factor. ATA was significantly more effective than all the other interventions in reducing platelet deposition in the stenotic vessels. We conclude that inhibition of Gp Ib/vWf interaction may be a more suitable target for antithrombotic therapy under conditions of high shear stress, like those produced in this model.

Early image acquisition after administration of indium-111 platelets in clinically suspected deep venous thrombosis.

Indium-111 platelet scintigraphy accurately detects acute deep venous thrombosis in asymptomatic high-risk patients and may be used as a surveillance test. However, its value in symptomatic patients and its accuracy early after platelet injection are not satisfactorily established. The latter is important for timely institution of therapy. Accordingly, 65 patients (67 limbs) with suspected deep venous thrombosis (symptom duration 8 +/- 10 days, mean +/- standard deviation) were prospectively studied with platelet scintigraphy and contrast venography. Platelets were labeled with 405 +/- 101 mCi indium-111 oxine. The labeling efficiency was 80 +/- 10%. All images were acquired within 120 minutes after intravenous administration of the platelet suspension. Both platelet scintigraphy and venography were interpreted independently by 2 blinded observers (for each technique). Five separate analyses were performed. Each scintigraphic reader was compared to each venographic reader. A fifth analysis--consisting of readings with blinded agreement of both readings of the platelet scans and both readings of the venograms--was performed. Interobserver agreement was 92% for venography and 79% for scintigraphy. Excluding anticoagulated patients, the sensitivity of platelet scintigraphy was between 38 and 46% and the specificity was between 92 and 100%. Thus, early imaging of labeled platelets for the diagnosis of symptomatic deep venous thrombosis carries a high specificity but a much lower sensitivity. It is speculated that the low sensitivity is related to the inactivity of the thrombus. This may suggest that early imaging will only be useful in patients whose symptoms are of recent onset.

Detection of platelet deposition at the site of peripheral balloon angioplasty using indium-111 platelet scintigraphy.

Restenosis after balloon angioplasty may be mediated through platelet deposition at the site of arterial dilatation. The purpose of this study was to determine whether platelet deposition at the site of dilatation could be detected using indium-111 platelet scintigraphy. Fifteen patients, aged 60 +/- 9 years, with iliac or femoral (n = 12), renal artery (n = 2) or distal aortic (n = 1) stenoses were studied. All patients received intravenous heparin at the time of dilatation. Labeled platelets containing 471 +/- 65 muCi indium-111 were injected 0.25 to 4 hours after dilatation and 1 to 24 hours after imaging. In 11 of 12 patients with iliac and femoral dilatations, focal uptake was demonstrated at the angioplasty site. In 4 patients (2 patients with renal, 1 patient with iliofemoral, and 1 with distal aortic stenoses), uptake at the dilatation sites was not detected. This preliminary study indicates that despite intravenous heparin, platelets accumulate at sites of balloon dilatation. Platelet scintigraphy may be useful in predicting sites of future narrowing after angioplasty and may be used to test the efficacy of antiplatelet therapy in retarding restenosis.

Double-blind, placebo-controlled trial of propranolol given once, twice and four times daily in stable angina pectoris: a multicenter study using serial exercise testing.

To determine if propranolol given twice daily (b.i.d.) or once daily (q.d.) was as effective as 4 times daily (q.i.d.) for treatment of stable angina pectoris, 78 patients with exercise-induced ST depression of 1.5 mm were randomized to q.i.d., b.i.d., q.d. and placebo groups. All patients received 5 tablets per day, and propranolol groups received 80, 160 and 320 mg/day on successive weeks. At weekly visits, patients underwent treadmill exercise testing before the 8:00 AM dose and at 2 and 9 hours afterward. Exercise duration (seconds) was significantly improved at the final visit compared with baseline by b.i.d. (120 +/- 36 [mean +/-] standard error of the mean p less than 0.001 n = 18) and q.i.d. (100 +/- 37, p less than 0.01; n = 17) regimens, but not by the q.d. (30 +/- 33; n = 18) and placebo regimens (27 +/- 37; n = 17). There was a significant decrease from baseline in the magnitude of ST depression at the final visit, measured at maximal common exercise duration in b.i.d. (-0.96 +/- 0.20 mm, p less than 0.001), q.i.d. (-0.84 +/- 0.20 mm, p less than 0.01) and q.d. (-0.58 +/- 0.18 mm, p less than 0.05) groups, but not in the placebo group (0.03 +/- 0.2 mm). Hourly heart rate by Holter was reduced in all 3 propranolol groups; however, the mean serum propranolol level was significantly lower just before the first dose with q.d. group (56 +/- 20 ng/ml) compared with b.i.d. and q.i.d. groups (146 +/- 22 and 119 +/- 28 ng/ml) with 320 mg/day (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic accuracy of indium-111 platelet scintigraphy in identifying left ventricular thrombi.

This study defines the optimum imaging time window after injection of labeled platelet suspension for detection on left ventricular (LV) thrombi, identifies the most useful imaging views, and determines the reproducibility of this technique. A total of 662 images obtained from 64 patients were analyzed retrospectively on 2 separate occasions by 3 observers blinded as to patient identity, view (right anterior oblique, anterior, left anterior oblique, and left lateral), and time after injection of the platelet suspension that the images were obtained (0 to 2, 3 to 4, and 5 to 6 days). Images were categorized as either positive or negative. In every case surgical or autopsy verification of the presence or absence of LV thrombus was possible. The best combination of sensitivity, specificity, and diagnostic accuracy was found in the 3- to 4-day period in the left anterior oblique view and was 54 +/- 5% (mean +/- standard deviation), 98 +/- 1%, and 85 +/- 2%, respectively. Sensitivity, specificity, and diagnostic accuracy were not enhanced by adding additional views (right anterior oblique, left lateral, and anterior) to the left anterior oblique view in the 3- to 4-day time period. However, using multiple views, localization of thrombi to the left ventricle was facilitated. In a second retrospective analysis, a comparison of day 0 with day 3 to 4 images enhanced sensitivity and accuracy to 65 (p less than 0.001) and 90% (not significant), respectively. Specificity was unchanged at 99%. Mean intra- and interobserver agreement was 91 and 88%, respectively. Thus, (1) indium-111 platelet scintigraphy is a reproducible and specific technique for identifying LV thrombus, and (2) we advise imaging on day 0 and again 3 to 4 days after injection of the platelet suspension in right anterior oblique, left anterior oblique, left lateral, and anterior views to maximize accuracy and to facilitate localization of LV thrombus.

Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

Transesophageal color flow Doppler imaging for aortic insufficiency in patients having cardiac operations.

Transesophageal color flow Doppler findings were studied in 30 patients with aortic insufficiency who had cardiac operations. Measurements were expressed as ratios of corresponding left ventricular outflow tract dimensions. Regurgitant jet proximal width ratio was significantly related to jet area ratio (r = 0.92) and correlated poorly with the degree of jet penetration into the left ventricular cavity (r = 0.32). The vectors of the regurgitant jets were variable. Nine patients had undergone aortography. Regurgitant jet proximal width and area ratios were significantly related to angiographic grade (r = 0.88 and 0.87, respectively) in these patients. We concluded that the esophagus offers a satisfactory transducer orientation for color flow Doppler assessment of aortic insufficiency.

Detection of active left ventricular thrombosis during acute myocardial infarction using indium-111 platelet scintigraphy.

Platelet scintigraphy with radioactive indium-111 may be used both to identify and to reflect the activity of thrombin in vivo in man. Forty-one patients with acute myocardial infarction were studied for active left ventricular thrombosis by platelet scintigraphy and followed until in-hospital death, discharge, or same-admission cardiac surgery for evidence of systemic embolization. A total of 4.7 +/- 2.4 X 10(9) platelets (mean +/- 1 SD) labelled with 381 mu Ci +/- 51 mu Ci of indium-111 was injected intravenously at 91 +/- 88 hours following the onset of chest pain. Patients were imaged in multiple views on the day of and three to four days after injection of the platelet suspension. Group 1 (n = 29) had transmural myocardial infarctions, of which 21 were anterior (peak total level of creatine phosphokinase [CPK], 2,272 +/- 2,026 IU; mean +/- 1 SD) and eight were inferior (CPK level, 1,673 +/- 589 IU). Group 2 (n = 12) had subendocardial myocardial infarctions (CPK level 799 +/- 751 IU). Those with subendocardial and transmural inferior myocardial infarctions had neither left ventricular thrombosis nor emboli. Ten (48 percent) of 21 with anterior transmural myocardial infarctions had left ventricular thrombosis by platelet scintigraphy. Three with and one without such thrombosis by scintigraphy had acute neurologic episodes. In the group with anterior myocardial infarctions, seven of ten patients with and four of 11 without left ventricular thrombosis received heparin subcutaneously (chi 2 = 1.22 [Yates correction]; p greater than 0.30). We conclude that platelet scintigraphy may be used to monitor antiplatelet and anticoagulant therapy in patients with anterior transmural myocardial infarctions who are at risk for left ventricular thrombosis and systemic embolization.

Vasoactive intestinal polypeptide in cardiac myxoma.

A case of left atrial myxoma is reported in which tumor tissue was found to contain high levels of vasoactive intestinal polypeptide. This finding further supports the concept that myxomas are true neoplasms and may explain some of the poorly understood clinical manifestations of this tumor.

Effect of short-duration constant exercise on permeability of cockerel aorta to 125I-albumin.

To determine quantitatively the effect of short duration constant exercise on the rate of uptake (U) of intravenously injected 125I-labeled cockerel albumin (A) by the aorta of the adult cockerel, 24 birds divided into age-matched pairs, each pair consisting of an exercised and nonexercised control bird, were studied. The time period of heparinization, anesthesia, and time from injection of A (each member of each pair received about 50 microCi from the same batch) to the death of the animal (T) was identical for each member of each pair. The exercised animal was exercised at a constant speed of 3.2 kph at 0 degrees elevation for between 2 and 5 min on a treadmill. U was defined as accumulated wall radioactivity (dpm)/plasma radioactivity (dpm/ml) X endothelial surface area (cm2) X T (s). Free 125I in the injectate amounted to 1.29 +/- 0.31% (mean +/- SD). Free 125I in the plasma and the wall in the exercise and control animals was not significantly different: plasma 0.84 +/- 0.34% (mean +/- SD) and 0.55 +/- 0.18 (P less than 0.20); wall 3.38 +/- 5.64% and 6.42 +/- 4.72 (P less than 0.04). Injected A remaining in the blood at between 8 and 16 min after intravenous injection was 83 +/- 8.7% (n = 10) in the exercised and 82 +/- 10% (n = 7) in the control (P less than 0.2). U was greater in the exercise group in 9 out of 12 matched pairs (P less than 0.05). We conclude that U increases for short periods of constant exercise.

Contemporary management of atrial fibrillation.

The incidence of atrial fibrillation approximately doubled for every 10-year increment in age in the Framingham Heart Study cohort; thus physicians will be faced with an increasing patient population with atrial fibrillation. Hypertension is observed to be the most common associated risk factor in both sexes. The management of patients with atrial fibrillation is evolving as a result of a number of published studies. Calcium channel blockers and beta-blockers are emerging as the preferred choices for rate control rather than digoxin. Low-dose anticoagulation therapy has shown beneficial effects not only in primary prevention, but also for secondary prevention of thromboembolism. Thus, patients who cannot be successfully cardioverted should be anticoagulated if there are no contraindications (Table 3) and if they do not fall into the low-risk group--defined as patients under the age of 65 without risk factors (hypertension, diabetes, previous stroke). Patients not eligible for anticoagulation should be on aspirin therapy. Patients with lone atrial fibrillation are not at higher risk for thromboembolism than the general population; therefore, they can be managed without anticoagulation or antiplatelet therapy. Antiarrhythmic treatment should be approached cautiously; amiodarone in low doses is the most effective and safe treatment, but this remains controversial.

Prevention of thromboembolism in patients with atrial fibrillation.

New insights into atrial physiology based on observations using transesophageal echocardiography are presented. The approach to anticoagulation of patients with both acute and chronic atrial fibrillation is reviewed within the context of the results of the major multicenter trials. These have provided some useful risk stratification guidelines for therapy. Presently available data suggest that the role of transesophageal echocardiography as a precardioversion screen is promising but requires further definition through clinical trials.