A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: the ATLAST trial.

OBJECTIVES: We performed a multicenter, double-blind placebo-controlled trial to examine the efficacy and safety of enoxaparin in patients at high risk for stent thrombosis (ST). BACKGROUND: The optimal antithrombotic regimen for such patients is unknown. METHODS: We randomized 1,102 patients with clinical, angiographic or ultrasonographic features associated with an increased risk of ST to receive either twice-daily injections of weight-adjusted enoxaparin or placebo for 14 days after stenting. All patients received aspirin and ticlopidine. The primary end point was a 30-day composite end point of death, myocardial infarction (MI) or urgent revascularization. RESULTS: The target enrollment for the study was 2,000 patients. However, the trial was terminated prematurely at 1,102 patients after interim analysis revealed an unexpectedly low event rate. The primary outcome occurred in 1.8% enoxaparin-treated patients versus 2.7% treated with placebo (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.29 to 1.5, p = 0.30); for death or MI the rates were 0.9% vs. 2.2%, respectively (OR 0.41, 95% CI 0.14 to 1.2, p =0.13); and for MI, 0.4% vs. 1.6%, respectively (OR 0.22, 95% CI 0.05 to 0.99, p = 0.04). The groups had comparable rates of major bleeding (3.3% for enoxaparin, 1.6% for placebo, p =0.08), but minor nuisance bleeding was increased with enoxaparin (25% vs. 5.1%, p < 0.001). CONCLUSIONS: The clinical outcomes of patients at increased risk of ST are more favorable than previously reported, rendering routine oral antiplatelet therapy adequate for most. However, given its relative safety and potential to reduce the risk of subsequent infarction, a 14-day course of enoxaparin may be considered for carefully selected patients.

Glycoprotein IIb/IIIa inhibitors and low-molecular-weight heparins: a combined role in coronary interventions?

Management strategies for acute coronary syndromes (ACS) are making increasing use of both low-molecular-weight heparins (LMWHs) and glycoprotein (GP) IIb/IIIa inhibitors. To date, however, relatively few studies have assessed the clinical potential of these two classes of agents in combination. There are theoretical grounds to expect LMWHs to be more effective than unfractionated heparin (UFH) in combination with GP IIb/IIIa inhibitors, since UFH, but not LMWH, activates platelets. The antiplatelet effects of GP IIb/IIIa inhibitors are therefore likely to be both more potent and more predictable when combined with LMWH. A recent study in more than 100 patients has demonstrated that a combination of dalteparin and the GP IIb/IIIa inhibitor abciximab provided effective anticoagulation in patients undergoing percutaneous coronary intervention (PCI), without causing significant bleeding or adverse events. Similar results were demonstrated in the National Investigators Collaborating on Enoxaparin (NICE-4) study using a combination of abciximab and enoxaparin in patients undergoing PCI. Of importance is the fact that there were no cases of severe thrombocytopenia in either LMWH study, although this is a recognized potential complication when UFH and abciximab are used in combination. Further studies are now warranted to confirm the efficacy of LMWH and GP IIb/IIIa inhibitors in combination, both for PCI and medical stabilization.

Readministration of abciximab in percutaneous coronary intervention.

Due to abciximab's chimeric monoclonal antibody structure, there have been concerns about the risks of anaphylaxis, attenuated efficacy, and immune-mediated thrombocytopenia when abciximab is readministered to patients. The issue of repeated treatment with abciximab is increasingly timely and important given that 30-35% of the almost 500,000 patients undergoing PCI annually in the United States receive abciximab. It is likely that this number will increase as lessons learned from recently completed trials with abciximab become integrated into day-to-day clinical practice. Accordingly, the purpose of this review is to identify the theoretic adverse effects of abciximab readministration and their potential mechanisms, analyze the available clinical data from patients re-treated with abciximab, and to offer some practical guidelines for abciximab readministration.

New intracoronary stent designs: form follows function versus function follows form.

Intracoronary stenting improves the acute and long-term safety and efficacy of percutaneous coronary interventions by minimizing the risks of abrupt closure and late restenosis. Enhanced designs of new coronary stents will continue to expand the spectrum of coronary anatomy and clinical settings amenable to nonsurgical revascularization. Improvements in deliverability, application to complex lesions, and durability of results are direct effects of improved design characteristics. Future design features may also include incorporating adjunctive therapies such as antithrombotic or antiproliferative agents with stent-based delivery systems. Results of new stent registries and randomized clinical trials are reviewed.

Comparison of six-month outcome of coronary artery stenting in patients <65, 65-75, and >75 years of age.

We studied 1,238 patients receiving 1,880 coronary stents. In-hospital outcomes were divided by age into <65 years (n = 747, group 1), 65 to 75 years (n = 326, group 2), and >75 years (n = 165, group 3). Procedural success was 97.2%, 95.1%, and 98.8% in groups 1, 2, and 3, respectively (p = NS). There was 1 death (group 1). Myocardial infarction occurred in 1.2%, 2.8%, and 1.8%, bypass surgery occurred in 0.9%, 1.8%, and 1.2%, and repeat balloon angioplasty in 0.3%, 0.6%, and 0% of patients in groups 1, 2, and 3, respectively (p = NS for all comparisons). Vascular complications occurred in 2.8%, 4.9%, and 6.1% in groups 1, 2, and 3, respectively (p <0.05). Six-month follow-up of patients was divided by age: <65 years (n = 564, group 1); 65 to 75 years (n = 221, group 2); and >75 years (n = 122, group 3). Event-free survival was 94.5%, 90.5%, and 89.3% for groups 1, 2, and 3, respectively (p = NS). Death occurred in 0.4%, 0.5%, and 1.6%; myocardial infarction occurred in 1.2%, 2.3%, and 1.6%, and target vessel revascularization in 4.3%, 8.6%, and 7.4% for groups 1, 2, and 3, respectively (p = NS for all comparisons). Thus, coronary stenting produced favorable in-hospital and 6-month outcomes in all 3 age groups. Age itself should not preclude patients from undergoing coronary stenting.

Abrupt (< 1 day), acute (< 1 week), and early (< 1 month) vessel closure at the angioplasty site. Morphologic observations and causes of closure in 130 necropsy patients undergoing coronary angioplasty.

While abundant clinical and angiographic data are available regarding features of acute or abrupt closure at the site of balloon angioplasty, little morphologic information is available. This study discusses morphologic-histologic causes for acute closure after angioplasty in 130 necropsy patients. Intimal-medial flaps, elastic recoil, and primary thrombosis were the three leading morphologic causes for closure. Data were subdivided into time categories: abrupt (< 1 day), acute (< 1 week), and early (< 1 month). Intimal-medial flaps remained the most common cause for angioplasty closure despite time from angioplasty to documented occlusion. Morphologic recognition of types and frequencies of angioplasty closure are discussed, and specific mechanical, pharmacologic, or combined treatments are reviewed.

Nonatherosclerotic causes of coronary artery narrowing--Part III.

Approximately 5% of patients with acute myocardial infarction do not have atherosclerotic coronary artery disease but have other causes for their luminal narrowing. The third part of this three-part review of nonatherosclerotic causes of coronary narrowing focuses on coronary vasculitis, infectious diseases, Kawasaki's disease, metabolic disorders, metastatic disease, and substance abuse (cocaine).

Nonatherosclerotic causes of coronary artery narrowing--Part II.

Part II of this three-part article on nonatherosclerotic causes of coronary heart disease focuses on myocardial bridges, coronary artery aneurysms, emboli, coronary dissection, and spasm as causes of luminal narrowing.

Nonatherosclerotic causes of coronary artery narrowing--Part I.

Approximately 5% of patients with acute myocardial infarction do not have atherosclerotic coronary artery disease but have other causes for their luminal narrowing. The first part of this three-part review of nonatherosclerotic causes of coronary narrowing focuses on congenital coronary artery anomalies, coronary fistula, and high take-off position of coronary ostia.

Late coronary artery stenosis regression within the Gianturco-Roubin intracoronary stent.

The late angiographic outcome of the Gianturco-Roubin intracoronary stent has not been well defined. To investigate serial changes within the stent, we studied 23 patients (15 men and 8 women, median age 63) who had late angiographic follow-up ( > 1 year) after undergoing Gianturco-Roubin stenting for angioplasty-associated acute or threatened native coronary artery closure. Coronary angiography before and after stenting, at 6-month follow-up, and at late return was analyzed with quantitative coronary angiography. The median time from stent deployment to late angiographic follow-up was 27 months. As expected, stenting significantly increased the median minimal lumen diameter (MLD) acutely from 1.0 to 2.46 mm. Median percent diameter stenosis decreased from 66% to 18%. Although at 6 months there was a significant loss of the acute gain (median MLD decreased from 2.46 to 1.9 mm), with a corresponding increase in percent stenosis from 18% to 31%, late angiography demonstrated lesion regression, median MLD increasing from 1.9 to 2.15 mm (p = 0.004), and percent stenosis decreasing from 31% to 21% (p = 0.0026). No patient had a significant decline in minimal lesion diameter, and 5 patients had a > 50% increase in MLD at late follow-up. Linear regression analysis of 6-month MLD and late lumen gain suggested that lesions with the greatest regression were those with the lowest lumen diameters at 6-month angiography. Late angiographic analysis demonstrated significant lesion regression within the Gianturco-Roubin stent, which was sometimes dramatic. In suggesting that coronary arteriography at 6 months may underestimate the late angiographic benefit of intracoronary stenting, these data have important clinical implications, and imply that patients with a stable clinical course and angiographic stent restenosis may often be followed rather than routinely redilated.

Indications for and applications of the Gianturco-Roubin coronary stent.

The Gianturco-Roubin coronary stent is approved for and effective in the management of acute or threatened closure after unsuccessful coronary intervention. Factors critical to successful stenting include patient and lesion selection, preprocedure identification of patients in potential need of stenting, selection of stent-compatible ancillary equipment, appropriate antiplatelet and anticoagulant therapy, postdeployment stent dilatation, and careful sizing of stents. Further refinements of technique and adjunctive drug therapy should continue to improve results and avoid acute complications. Published clinical experience and potential future applications are discussed.

Labeling of human clots in vitro with an active-site mutant of t-PA.

Prompt detection of acute thrombosis and its response to treatment with thrombolytic agents generally require angiography. Scintigraphic approaches with labeled antibodies to or components of the coagulation and fibrinolytic systems have been disappointing because of prolonged circulating half-lives of tracers and relatively slow or limited binding to thrombi. Accordingly, we developed and characterized a thrombolytically inactive, active-site mutant (Ser-478----Thr) of tissue-type plasminogen activator (t-PA) designed to detect thrombi in vivo. Binding of iodine-125-(125I) labeled Ser----Thr t-PA to thrombi in vitro was time- and concentration-dependent, and specific judging from inhibition by pre-incubation with anti-t-PA IgG. Clearance of 125I-labeled mutant t-PA in rabbits was rapid and biexponential (alpha t1/2 = 1.9 +/- 0.4 min, beta t1/2 = 39.8 +/- 11.2 min). Thus, the amidolytically inactive mutant of t-PA designed binds rapidly and specifically to human thrombi in vitro and is cleared rapidly from the circulation in vivo--properties rendering it attractive as a potentially useful clot imaging agent.

The nature of synergy between tissue-type and single chain urokinase-type plasminogen activators.

Enhancement of thrombolysis with combinations of tissue-type and single chain urokinase plasminogen activators (t-PA and scu-PA) has been demonstrated in vivo but has not been seen consistently in vitro. This study was designed to characterize interactions between t-PA and scu-PA with respect to rate of and extent of thrombolysis in vitro and to delineate mechanisms responsible. Combinations of t-PA and scu-PA at selected concentrations synergistically enhanced thrombolysis in vitro compared with thrombolysis induced by either activator alone. Enhanced thrombolysis did not occur at the expense of fibrin specificity since the extent of fibrinogenolysis and consumption of alpha 2-antiplasmin were significantly less with synergistic combinations of t-PA and scu-PA compared with equi-effective concentrations of either activator alone. Attenuation of complex formation of t-PA and two chain u-PA (tcu-PA), formed from scu-PA, with plasma proteins did not appear to contribute to enhancement of thrombolysis as assessed by fibrin autography. Binding of 125I-t-PA to thrombi was increased by 27% at 1 hr and by 21% at 2 hr in the presence of scu-PA (p less than 0.001 for both). Conversion of scu-PA to tcu-PA was enhanced when thrombi were exposed to scu-PA in the presence of t-PA. Results of this study indicate that t-PA and scu-PA at selected concentrations enhance thrombolysis in vitro synergistically without compromising fibrin specificity. Enhanced binding of t-PA to thrombi in the presence of scu-PA and enhanced conversion of scu-PA to tcu-PA appear to contribute to synergy between t-PA and scu-PA for thrombolysis.

Characterization of interaction of active-site serine mutants of tissue-type plasminogen activator with plasminogen activator inhibitor-1.

To define determinants of interactions of tissue-type plasminogen activator (t-PA) with plasminogen activator inhibitor type-1 (PAI-1), we utilized site-directed mutagenesis to substitute either threonine or glycine for the active-site serine of tissue-type plasminogen activator. Assays of conditioned media of transfected cells demonstrated that the threonine substitution markedly decreased but did not entirely abolish plasminogen activating activity. In contrast, the glycine substitution yielded a mutant with absolutely no detectable plasminogen activating activity. Wild-type t-PA formed stable complexes with PAI-1. However, even when exogenous inhibitor was present in the medium or purified mutant was added to plasma that had been rendered PAI-1-rich in vivo, the mutants were present in the free form exclusively judging from results of fibrin autography and Western blot analysis. Thus, despite maintenance of some residual plasminogen-activating activity associated with preservation of the hydroxyl group at the active site, the threonine mutant did not form stable complexes with inhibitor. The glycine mutant, developed so that steric hindrance or other unfavorable interactions at the modified active site would be minimal, was similarly incapable of forming complexes with PAI-1. These results show that the presence of an active site serine residue is necessary for formation of stable complexes between t-PA and PAI-1.

Lack of interference by heparin with thrombolysis or binding of tissue-type plasminogen activator to thrombi.

Coronary thrombolysis with t-PA is generally implemented with concomitant administration of heparin. However, results of studies in vitro suggest that heparin competes with fibrin for binding of tissue-type plasminogen activator (t-PA), augments activation of free plasminogen, decreases fibrin specificity, and impairs thrombolysis. To define the biological implications of these observations, we characterized effects of therapeutic concentrations of heparin on the binding of t-PA to thrombi formed in whole blood, effects of heparin on activation of plasminogen by t-PA in plasma, and effects of heparin on thrombolysis induced by t-PA in a clot lysis system designed to simulate conditions in vivo. The amount of t-PA bound to thrombi was not affected by heparin (0, 0.5, 1.0, and 5.0 U/mL). When t-PA activity was selectively and irreversibly inhibited by D-Phe-Pro-Arg-chloromethyl ketone (PPACK) the amount of t-PA-PPACK bound was similarly unaffected by heparin. Thrombolysis measured by 125I-fibrin(ogen) release and by reduction of mass of thrombi were not altered by heparin. Heparin did not affect plasminogen consumption induced by t-PA. Plasma concentrations of alpha-2-antiplasmin after exposure of blood to t-PA were less depressed with increasing concentrations of heparin. Thus, heparin in therapeutic concentrations does not interfere with binding of t-PA to thrombi, augment activation of free plasminogen, or inhibit thrombolysis. Accordingly, it appears likely that concomitant administration of heparin will not impair thrombolysis with t-PA implemented clinically.

Biochemical determinants of clearance of tissue-type plasminogen activator from the circulation.

Biochemical modification of tissue-type plasminogen activator (t-PA) designed to alter pharmacokinetics and pharmacodynamics offers promise for development of pharmaceuticals particularly suitable for treatment of specific disorders and for induction of coronary thrombolysis by intramuscular as well as intravenous administration. Accordingly, to identify biochemical determinants of clearance of t-PA from the circulation, we injected rabbits intravenously with three different preparations of t-PA synthesized from the same human gene and expressed in Chinese hamster ovary cells cultured under disparate conditions. Influences of glycosylation on clearance were defined by experiments with enzymatically treated t-PA in which clearance was assessed with concomitant administration of selected neoglycoproteins that compete with t-PA for specific glycoprotein receptors. The role of an intact active catalytic site, as reflected by differences in clearance with and without prior treatment of t-PA with the protease inhibitor PPACK, was defined also. Results indicate that clearance is altered by inhibition of the active site and that the nature and extent of glycosylation--not evident simply by analysis of peptide structure--influence clearance as well. These findings suggest that mannose/N-acetylglucosamine-specific glycoprotein receptors expressed on hepatic reticuloendothelial cells participate in clearance of t-PA from the circulation but that galactose-specific glycoprotein receptors probably do not. The observations may explain differences in clearance seen with different preparations of t-PA that have been seen in clinical pilot studies and may identify biochemical determinants of clearance amenable to modification for development of agents with potentially desirable, specific biological properties.