Steven P. Ball

Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: Observations from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study

OBJECTIVES The purpose of this study was to determine the incidence and demographic characteristics of patients experiencing cardiac rupture after thrombolytic and adjunctive anticoagulant therapy and to identify possible associations between the mechanism of thrombin inhibition (indirect, direct) and the intensity of systemic anticoagulation with its occurrence. BACKGROUND Cardiac rupture is responsible for nearly 15% of all in-hospital deaths among patients with myocardial infarction (MI) given thrombolytic agents. Little is known about specific patient- and treatment-related risk factors. METHODS Patients (n = 3,759) with MI participating in the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9A and B trials received intravenous thrombolytic therapy, aspirin and either heparin (5,000 U bolus, 1,000 to 1,300 U/h infusion) or hirudin (0.1 to 0.6 mg/kg bolus, 0.1 to 0.2 mg/kg/h infusion) for at least 96 h. A diagnosis of cardiac rupture was made clinically in patients with sudden electromechanical dissociation in the absence of preceding congestive heart failure, slowly progressive hemodynamic compromise or malignant ventricular arrhythmias. RESULTS A total of 65 rupture events (1.7%) were reported-all were fatal, and a majority occurred within 48 h of treatment Patients with cardiac rupture were older, of lower body weight and stature and more likely to be female than those without rupture (all p < 0.001). By multivariable analysis, age >70 years (odds ratio [OR] 3.77; 95% confidence interval [CI] 2.06, 6.91), female gender (OR 2.87; 95% CI 1.44, 5.73) and prior angina (OR 1.82; 95% CI 1.05, 3.16) were independently associated with cardiac rupture. Independent predictors of nonrupture death included age >70 years (OR 3.68; 95% CI 2.53, 5.35) and prior MI (OR 2.14; 95%, CI 1.45, 3.17). There was no association between the type of thrombin inhibition, the intensity of anticoagulation and cardiac rapture. CONCLUSIONS Cardiac rupture following thrombolytic therapy tends to occur in older patients and may explain the disproportionately high mortality rate among women in prior dinical trials. Unlike major hemorrhagic complications, there is no evidence that the intensity of anticoagulation associated with heparin or hirudin administration influences the occurrence of rupture.

A randomized, multicenter trial of weight-adjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease

BACKGROUND Therapy with intravenous unfractionated heparin improves clinical outcome in patients with active thromboembolic disease, but achieving and maintaining a therapeutic level of anticoagulation remains a major challenge for clinicians. METHODS A total of 113 patients requiring heparin for at least 48 hours were randomly assigned at 7 medical centers to either weight-adjusted or non-weight-adjusted dose titration. They were separately assigned to either laboratory-based or point-of-care (bedside) coagulation monitoring. RESULTS Weight-adjusted heparin dosing yielded a higher mean activated partial thromboplastin time (aPTT) value 6 hours after treatment initiation than non-weight-adjusted dosing (99.9 vs 78.8 seconds; P =.002) and reduced the time required to exceed a minimum threshold (aPTT >45 seconds) of anticoagulation (10.5 vs 8.6 hours; P =.002). Point-of-care coagulation monitoring significantly reduced the time from blood sample acquisition to a heparin infusion adjustment (0.4 vs 1.6 hours; P <.0001) and to reach the therapeutic aPTT range (51 to 80 seconds) (16.1 vs 19.4 hours; P =.24) compared with laboratory monitoring. Although a majority of patients participating in the study surpassed the minimum threshold of anticoagulation within the first 12 hours and reached the target aPTT within 24 hours, maintaining the aPTT within the therapeutic range was relatively uncommon (on average 30% of the overall study period) and did not differ between treatment or monitoring strategies. CONCLUSIONS Weight-adjusted heparin dosing according to a standardized titration nomogram combined with point-of-care coagulation monitoring using the BMC Coaguchek Plus System represents an effective and widely generalizable strategy for managing patients with thromboembolic disease that fosters the rapid achievement of a desired range of anticoagulation. Additional work is needed, however, to improve on existing patient-specific strategies that can more effectively sustain a therapeutic state of anticoagulation.

Peak creatine kinase as a measure of effectiveness of thrombolytic therapy in acute myocardial infarction

As part of the National Heart, Lung, and Blood Institute multicenter Thrombolysis in Myocardial Infarction Trial, the time to peak plasma creatine kinase (CK) activity as a marker of reperfusion in 272 patients with validated acute myocardial infarction was analyzed. Patients were treated with either tissue-type plasminogen activator or streptokinase by intravenous administration. All patients underwent acute coronary angiography. The infarct-related artery was identified and thrombolytic therapy administered. Reperfusion at 90 minutes was documented by angiography. CK was determined before institution of therapy and every 4 hours thereafter for the first 24 hours. Patients were classified into 3 groups for comparative purposes: group 1--occlusion with no reperfusion (n = 119); group 2--occlusion with reperfusion (n = 98); and group 3--subtotal occlusion (n = 55). Early (within 4 hours after treatment) and late (more than 16 hours after treatment) peaking of CK differentiated patients with drug-induced perfusion from those without reperfusion. Although peak CK between 5 and 11 hours after drug treatment did suggest perfusion through the infarct-related artery, it did not differentiate between drug-induced and spontaneous reperfusion. Clinically, early peak CK is a useful noninvasive means of assessing coronary artery patency. However, in clinical trials assessing drug therapy, the use of peak CK may overestimate drug effectiveness by including patients with spontaneous reperfusion.

Bedside coagulation monitoring in heparin-treated patients with active thromboembolic disease: A coronary care unit experience

Patients with active venous and arterial thromboembolic disorders are known to benefit from systemic anticoagulation with heparin. Clinical studies have shown, however, that therapeutic anticoagulation is rarely achieved rapidly and often is not maintained over time. Prolonged laboratory turnaround time of the activated partial thromboplastin time (aPTT) may contribute directly to these common problems. A total of 272 aPTT determinations were performed on 120 heparin-treated patients admitted to the coronary care unit. The time from sample collection to data availability was 126 +/- 84 minutes with standard laboratory aPTT testing. In contrast, a bedside coagulation device provided an aPTT within 3 minutes (p < 0.001). Subtherapeutic aPTT values (< 65 seconds) were documented in 21% of all patients; in each, the heparin dose was changed and a repeat aPTT was required. In a separate study of 33 heparinized patients randomized to either bedside or central laboratory aPTT testing (264 aPTT determinations), the time to achieve a therapeutic state of systemic anticoagulation was 8.2 hours and 18.1 hours, respectively (p < 0.005). The time from aPTT determination to a decision regarding heparin titration adjustments was 14.5 minutes and 3 hours with bedside and laboratory testing, respectively (p < 0.001). Thus bedside coagulation monitoring provides a convenient, rapid, and accurate assessment of systemic anticoagulation among heparin-treated patients with active thromboembolic disease in the coronary care unit. This technology warrants further clinical investigation.

Impact of thrombolytic therapy on left ventricular mural thrombi in acute myocardial infarction

Abstract Left ventricular (LV) mural thrombi have long been recognized as a complication of acute myocardial infarction (AMI). Recent echocardiographic studies suggest an incidence of 2 to 18% in patients with AMI. Anterior infarctions are found to have a much higher incidence of mural thrombus than inferior infarctions. 1 Previous reports have noted conflicting results regarding the effect of thrombolysis on the formation of LV mural thrombi after AMI. 2–4 The aim of this study was 2-fold: to examine if systemic thrombolytic therapy using either tissue plasminogen activator or streptokinase reduces the incidence of LV mural thrombi early after AM1 compared with conventional treatment, and to determine if reperfusion of the infarct-related artery was associated with a lower incidence of LV mural thrombi.

Hemorrhagic potential of combined diltiazem and recombinant tissue-type plasminogen activator administration

In the Thrombolysis in Myocardial Infarction (TIMI) phase II study, use of calcium channel antagonists at study entry was associated with an increased risk of intracerebral hemorrhage. Whether the observed association was due solely to chance, underlying cerebrovascular disease, or an effect of calcium channel antagonists themselves was not determined. Accordingly, blood loss from standardized ear incisions was measured in six groups of anesthetized New Zealand white rabbits: (1) saline control, (2) intravenous diltiazem (20 micrograms/kg/min x 60 minutes), (3) intravenous recombinant tissue-type plasminogen activator (rTPA) (1.0 mg/kg over 60 minutes, 10% bolus), (4) diltiazem plus rTPA, (5) diltiazem daily for 3 consecutive days, and (6) diltiazem (3 days) plus rTPA given on day 3. The combination of rTPA plus diltiazem (3 days) resulted in significantly more blood loss than rTPA alone, diltiazem (60-minute infusion), or rTPA plus diltiazem (60-minute infusion) (p = 0.003). Similarly, diltiazem (3 days) resulted in more blood loss than either agent alone or rTPA plus diltiazem (60-minute infusion) (p < 0.05). Thus, in this animal model, prolonged exposure to diltiazem with or without rTPA was associated with increased bleeding. The potential for chronic use of oral calcium channel antagonist to increase hemorrhagic risk after rTPA administration requires further investigation.

Inhibition of Platelet-Dependent Prothrombinase Activity and Thrombin Generation by Glycoprotein IIb/IIIa Receptor-Directed Antagonists: Potential Contributing Mechanism of Benefit in Acute Coronary Syndromes

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrodes buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

Platelet activation determined by flow cytometry persists despite antithrombotic therapy in patients with unstable angina and non-Q-wave myocardial infarction

Background: Current strategies in the treatment of patients with acute coronary syndromes include antiplatelet agents and thrombin antagonists, most commonly aspirin and heparin, respectively. Cardiac events, however, occur despite what is considered to be maximal medical treatment.Methods: We determined the percentage of activated platelets in whole blood samples taken from 22 patients with unstable angina and non-Q-wave myocardial infarction participating in the TIMI III B trial. Platelet activation was assessed using a monoclonal antibody to the surface-expressed α-granule protein, P-selectin, and flow cytometry. All patients received a full complement of antiischemic medications as well as intravenous heparin and oral aspirin, and were then randomized to tissue plasminogen activator or placebo.Results: Platelet activation prior to randomization was increased threefold to fourfold compared with healthy volunteers (11.4 ± 11.4% vs. 2.5 ± 2.0%; p < 0.01). Serial measurements performed 12, 24, 48, and 96 hours after treatment initiation revealed that platelet activation persisted. No differences in patients experiencing recurrent ischemic events (n=9) or those randomized to a 90-minute, accelerated infusion of tissue plasminogen activator (n=12) were observed.Conclusions: A modest degree of platelet activation is seen for at least 96 hours and possibly longer in patients with unstable angina and non-Q-wave myocardial infarction, despite being treated with intravenous heparin and oral aspirin. These findings support current efforts to identify more potent and selective antithrombotic treatment strategies.

Dynamic nature of thrombin generation, fibrin formation, and platelet activation in unstable angina and non-Q-wave myocardial infarction

BackgroundThrombin and platelets are directly involved in arterial thrombosis, typically occurring at sites of atherosclerotic plaque rupture among patients with acute coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has important clinical implications.MethodsFibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2), plasma markers of fibrin formation (thrombin activity) and thrombin generation, and platelet activation, determined by the recognition of a surface-expressed platelet α-granule protein, P-selectin, using flow cytometry, were measured in 36 consecutive patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B trial.ResultsThrombin generation (TAT 12.1 ± 17.8 ng/ml vs. 3.4 ± 1.0 ng/ml; F1.2 0.19 ± 0.14 nmol/1 vs. 0.12 ± 0.8 nmol/1), fibrin formation (FPA 15.8 ± 23.5 ng/ml vs. 7.5 ± 2.3 ng/ ml), and platelet activation) 10.6 ± 2.4% vs. 2.5 ± 2.0%) were increased significantly in patients compared with healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma FPA levels, did not correlate with the percentage of activated platelets (r=− .10, p=0.69). Thrombin generation and platelet activation also did not correlate. A statistically insignificant trend between TAT and platelet activation was observed (r=.42, p=0.07); however, even with TAT levels in excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet activation was increased by only 1.7-fold.ConclusionsThrombin generation, fibrin formation, and platelet activation are increased modestly among patients with unstable angina and non-Q-wave myocardial infarction. Despite the involvement of platelets and coagulation proteins in arterial thrombotic processes, their relative contributions may vary, providing a pathophysiologic basis for the dynamic expression of disease and response to treatment observed commonly in clinical practice.

Enoxaparin, a low molecular weight heparin, inhibits platelet-dependent prothrombinase assembly and activity by factor-Xa neutralization.

Background: The available evidence suggests strongly that intravascular thrombosis is mediated predominantly by tissue-factor and its activation of factor X, which in the presence of factor Va, calcium, and phospholipid (prothrombinase complex) effectively converts prothrombin to thrombin. In vitro experiments have shown that low molecular weight heparins (LMWHs) have greater anti-Xa activity than unfractionated heparin; however, it remains unclear as to whether their antithrombotic effects in vivo are determined by a similar mechanism. We determined the ability of plasma obtained from patients with either unstable angina or non-ST segment elevation myocardial infarction (MI) receiving the LMWH enoxaparin (anti Xa:IIa ratio 3:1) to inhibit tissue factor-mediated thrombin generation and to inactivate platelet prothrombinase.Methods: Platelet rich plasma was prepared by suspending washed donor platelets in the plasma of 7 patients participating in the TIMI 11A study. Samples were obtained before, 1 hour after a 30-mg IV bolus of enoxaparin and 6 hours after the third subcutaneous injection (1.0–1.25 mg/kg given subcutaneously every 12 hrs). Tissue factor (0.1 ng/ml) and 10 mM CaCl2 were added to initiate extrinsic coagulation. At timed intervals prothrombin activation fragment 1.2 (F1.2) levels (thrombin generation) were measured using an ELISA technique. Inactivation of reformed platelet prothrombinase by samples obtained at the same time points was also determined.Results: Patient plasma obtained 1 hr after treatment initiation and 6 hours after the third subcutaneous injection inhibited tissue factor mediated prothrombinase assembly by 31% and 11%, respectively and platelet prothrombinase activity by 27% and 22%, respectively.Conclusion: We conclude that enoxaparin in plasma concentrations achieved routinely in clinical practice is able to: (1) inhibit tissue factor mediated extrinsic coagulation by preventing platelet surface prothrombinase assembly, and (2) inactivate platelet prothrombinase activity and resulting thrombin generation. These observations suggest that a LMWHs anti-Xa activity (and anti-Xa:IIa profile) is important in determining its overall antithrombotic potential. Clinical trials comparing agents with differing anti-Xa:IIa properties will be required, however, to provide proof of concept.