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)

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.

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.

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)

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.