Paul R. Eisenberg

Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial.

OBJECTIVES The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size. BACKGROUND Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects. METHODS The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke). RESULTS In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89). CONCLUSIONS Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.

Clinical evaluation compared to pulmonary artery catheterization in the hemodynamic assessment of critically ill patients

Although pulmonary artery (PA) catheterization is frequently employed in the management of critically ill patients, there is little documentation that the information obtained alters patient management. This study evaluated prospectively this question in 103 PA catheterizations. Before catheterization, physicians were asked to predict the range of several hemodynamic variables, the presumed diagnosis, and their plan for therapy. After catheterization, each chart was reviewed. The hemodynamics at the time of catheterization and therapy within 8 h of catheterization were noted. Pulmonary artery occlusive (wedge) pressure (WP) was correctly predicted 30% of the time. Cardiac output, systemic vascular resistance (SVR), and right atrial pressure (RAP) were correctly predicted approximately 50% of the time. There was no significant difference in the ability to predict hemodynamics of subgroups with either hypotension or impaired oxygenation. After catheterization, planned therapy was altered in 58% of the cases. Unanticipated therapy was added in 30% of the cases. This study documents the difficulty of predicting accurately hemodynamics based solely on clinical evaluation. Thus, the information obtained by catheterization often leads to alterations in the therapeutic plan. We suggest that PA catheterization is both indicated and useful in the management of critically ill patients.

Paradoxic elevation of fibrinopeptide A after streptokinase: Evidence for continued thrombosis despite intense fibrinolysis

Elevated levels of fibrinopeptide A, a marker of thrombin activity associated with acute myocardial infarction, have been found to decrease after administration of streptokinase when reperfusion occurs. In contrast, in patients without reperfusion and those with reocclusion after streptokinase therapy, fibrinopeptide A remains elevated. In the present study early serial measurements of fibrinopeptide A were used to further characterize this paradoxic increase in thrombin activity after streptokinase and to characterize its response to heparin. In 19 patients with acute myocardial infarction fibrinopeptide A was elevated to 82.3 +/- 43.5 ng/ml (mean +/- SE) before therapy. Thirty minutes after the initiation of streptokinase, fibrinopeptide A increased to 300.1 +/- 117.4 ng/ml (p less than 0.01), consistent with extensive thrombin activity. Fibrinopeptide A remained elevated until 15 minutes after a heparin bolus injection when levels decreased to 15% of the poststreptokinase value (49.2 +/- 13.3 ng/ml) (p less than 0.001). These data document a prompt paradoxic increase in thrombin activity after administration of streptokinase that may be responsible for failure of therapy in some patients.

Fibrinopeptide A: a marker of acute coronary thrombosis.

To determine whether coronary thrombosis in vivo is reflected by elevations in levels of fibrinopeptide A (FPA) in plasma, we sequentially characterized plasma FPA levels associated with evolving infarction in patients admitted to the cardiac care unit early after the onset of symptoms, in patients with transmural infarction admitted later, and in patients with nontransmural infarction. Studies were also performed in patients in whom the diagnosis of infarction was suspected but subsequently excluded. FPA values were significantly higher in patients with transmural infarction (42.3 +/- 11.2 ng/ml [mean +/- SEM], n = 53) compared with those in patients with nontransmural infarction (4.8 +/- 1.6 ng/ml, n = 17) or with those in patients in whom infarction was subsequently excluded as a diagnosis (3.5 +/- 0.6 ng/ml, n = 17, p less than .01 for both). Elevations in FPA level were greatest in patients with transmural infarction from whom samples were obtained soon after the onset of symptoms. Thus, in 39 patients from samples were obtained within 10 hr after the onset of symptoms, FPA levels were significantly higher than in 14 patients from whom samples were obtained initially more than 10 hr after the onset of symptoms (55.5 +/- 14.7 vs 4.9 +/- 1.4 ng/ml, p less than .01). In 30 of the 39 patients with evolving transmural infarction from whom samples were obtained within the first 10 hr after the onset of symptoms, the level of FPA was greater than 8 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of factor Xa in determining the procoagulant activity of whole-blood clots.

The binding of thrombin to fibrin is thought to be an important mechanism by which thrombi exhibit procoagulant activity; however, the extent to which other procoagulants are associated with thrombi has not been previously defined. This study was designed to determine whether clotting factors other than thrombin are bound to whole-blood clots and can thereby contribute to significant procoagulant activity. Clots formed in vitro from human blood exhibited minimal thrombin activity when incubated in plasma depleted of vitamin K-dependent factors by barium-citrate adsorption, as indicated by increases in the concentration of fibrinopeptide A (FPA), a marker of fibrin formation, to 72 nM after 30 min. Incubation of clots in barium-absorbed plasma repleted with 0.9 microM human prothrombin under the same conditions resulted in marked increases in the concentration of FPA (> 1,000 nM) and clotting by 30 min. The increases in FPA were attributable to activation of the added prothrombin by clot-associated Factor Xa, judging from concomitant increases in the concentration of prothrombin fragment 1.2. Similar results were obtained with thrombi induced in the axillary arteries of dogs by vascular injury and incubated with plasma in vitro. Activation of prothrombin was inhibited in a dose-dependent manner by tick anticoagulant peptide, a direct inhibitor of Factor Xa, at concentrations of 0.5-5.0 microM. Clot-associated Factor Xa activity was resistant to inhibition by anti-thrombin III, judging from the lack of inhibition of prothrombin activation during incubation of clots in plasma containing heparin pentasaccharide, an anti-thrombin III-mediated inhibitor of Factor Xa. Thus, the activity of Factor Xa appears to be an important determinant of the procoagulant activity of whole-blood clots and arterial thrombi, and is resistant to inhibition by anti-thrombin III-dependent inhibitors.

Prior aspirin use predicts worse outcomes in patients with non–ST-elevation acute coronary syndromes

Aspirin is beneficial in the prevention and treatment of cardiovascular events, but patients who have events while taking aspirin may have worse outcomes than those not on aspirin. We investigated the association between prior aspirin use and clinical outcomes in 9,461 patients with non-ST-elevation acute coronary syndromes enrolled in the Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, before and after adjustment for baseline factors. We also examined whether eptifibatide has a differential treatment effect in prior aspirin users. Prior aspirin users were less likely to have an enrollment myocardial infarction (MI) (vs unstable angina) (43.9% vs 48.8%, p = 0.001) but more likely to have death or MI at 30 days (16.1% vs 13.0%, p = 0.001) and at 6 months (19.9% vs 15.9%, p = 0.001). After adjustment, prior aspirin users remained less likely to have an enrollment MI (odds ratio 0.88, 95% confidence interval 0.79 to 0.97) and more likely to have death or MI at 30 days (odds ratio 1.16, 95% confidence interval 1.00 to 1.33) but not at 6 months (odds ratio 1.14, 95% confidence interval 0.98 to 1.33). In a multivariable model, eptifibatide did not have a different treatment effect in prior aspirin users compared with nonusers (p = 0.534). Prior aspirin users had fewer enrollment MIs but worse long-term outcomes than nonusers. We found no evidence for a different treatment effect of eptifibatide in prior aspirin users.

Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension.

Although the mechanisms involved in the pathophysiology of primary pulmonary hypertension have not yet been delineated, thrombosis has been implicated. This study was designed to determine whether thrombin activity as reflected by plasma concentrations of fibrinopeptide A (FPA), a marker of the action of thrombin on fibrinogen, is increased in patients with primary pulmonary hypertension. To evaluate fibrinolytic activity, we measured plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and cross-linked fibrin degradation products. We studied 31 patients with primary pulmonary hypertension. Plasma FPA concentrations measured by radioimmunoassay, were elevated to 87.4 +/- 36.9 ng/ml (mean +/- SEM). Fifteen minutes after administration of heparin (5,000 U), FPA concentrations decreased to 6.8 +/- 1.4 ng/ml (p less than 0.001 compared with preheparin levels). In 21 of 30 patients (70%), FPA concentrations after heparin administration were less than half the preheparin levels, a response consistent with inhibition of thrombin by heparin and the short half-life of FPA. Despite evidence for marked thrombin activity, plasma concentrations of cross-linked fibrin degradation products were normal in all but four patients. Plasminogen activator inhibitor-1 activity was elevated in 19 of the 27 patients in whom it was measured, potentially limiting the fibrinolytic response. The elevations of FPA indicate that thrombin activity is increased in vivo in patients with primary pulmonary hypertension. Thus, sequential assays of plasma markers of thrombosis and fibrinolysis in vivo may help identify those patients who may benefit from treatment with anticoagulants.

Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis

Factors responsible for initial success or failure of coronary thrombolysis and persistent recanalization or early reocclusion have not been thoroughly elucidated. Both adequate initial clot lysis and preclusion of rethrombosis are required. Failure may reflect clot lysis followed immediately or somewhat later by rethrombosis. To determine whether differences in the intensity and persistence of the activation of thrombin are determinants of success or failure of recanalization, plasma fibrinopeptide A, a fibrinogen product liberated by thrombin, was serially assayed in 19 patients treated with intravenous streptokinase. In patients exhibiting recanalization (n = 9), plasma fibrinopeptide A decreased after administration of streptokinase but before administration of heparin. In patients without initially apparent recanalization, fibrinopeptide A increased, suggesting ongoing thrombosis, and subsequently decreased promptly after heparin. In patients with initial recanalization followed by overt reocclusion the pattern was different. Despite recanalization, fibrinopeptide A continued to rise markedly. Elevations persisted despite administration of heparin. Thus, inhibition of activation of thrombin is associated with successful recanalization. Conversely, persistent activation of thrombin may be a predisposing factor to both apparent initial failure of recanalization and overt early reocclusion.

Activation of prothrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator☆

Increases in thrombin activity in patients given fibrinolytic agents for acute myocardial infarction have been shown to be important in limiting the ultimate success of coronary thrombolysis. The present study was designed to determine whether increases in thrombin activity reflect, in part, activation of prothrombin accompanying thrombolysis. Plasma concentrations of prothrombin fragment 1.2, a polypeptide released when prothrombin is activated by factor Xa, were measured in 22 patients with acute myocardial infarction before and after treatment with 100 mg of recombinant tissue-type plasminogen activator (rt-PA). Concentrations of prothrombin fragment 1.2 increased from 0.83 +/- 1.1 nM (mean +/- SD) before rt-PA infusion to 1.5 +/- 1.5 nM 2 h after initiation of the infusion (p less than 0.05). After a 5,000-U intravenous dose of heparin given at the end of the infusion of rt-PA, concentrations of prothrombin fragment 1.2 decreased from 1.8 +/- 1.5 to 1.1 +/- 0.9 nM (n = 20, p less than 0.05), although values were still increased compared with concentrations before rt-PA. These results indicate that thrombin activity increases in patients given rt-PA at least in part because of activation of the coagulation system leading to activation of prothrombin. Thus, inhibition of the reactions involving coagulant proteins that lead to activation of prothrombin may be of value as conjunctive treatment to potentiate the efficacy of pharmacologic thrombolysis.

In vitro characterization of a novel, tissue-targeted ultrasonic contrast system with acoustic microscopy

Targeted ultrasonic contrast systems are designed to enhance the reflectivity of selected tissues in vivo [Lanza et al., Circulation 94, 3334 (1996)]. In particular, these agents hold promise for the minimally invasive diagnosis and treatment of a wide array of pathologies, most notably tumors, thromboses, and inflamed tissues. In the present study, acoustic microscopy was used to assess the efficacy of a novel, perfluorocarbon based contrast agent to enhance the inherent acoustic reflectivity of biological and synthetic substrates. Data from these experiments were used to postulate a simple model describing the observed enhancements. Frequency averaged reflectivity (30-55 MHz) was shown to increase 7.0 +/- 1.1 dB for nitrocellulose membranes with targeted contrast. Enhancements of 36.0 +/- 2.3 dB and 8.5 +/- 0.9 dB for plasma and whole blood clots, respectively, were measured between 20 and 35 MHz. A proposed acoustic transmission line model predicted the targeted contrast system would increase the acoustic reflectivity of the nitrocellulose membrane, whole blood clot, and fibrin plasma clot by 2.6, 8.0, and 31.8 dB, respectively. These predictions were in reasonable agreement with the experimental results of this paper. In conclusion, acoustic microscopy provides a rapid and sensitive approach for in vitro chracterization, development, and testing of mathematical models of targeted contrast systems. Given the current demand for targeted contrast systems for medical diagnostic and therapeutic use, the use of acoustic microscopy may provide a useful tool in the development of these agents.