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Biomedical subjects

A M Lincoff

Publications and source records attributed to A M Lincoff.

At least 91 records · Page 5Linked to original sources
PubMed1998

Abciximab therapy and unplanned coronary stent deployment: favorable effects on stent use, clinical outcomes, and bleeding complications. EPILOG Trial Investigators.

BACKGROUND: The clinical and angiographic demographics of patients requiring unplanned coronary stent deployment and the optimal adjunct pharmacotherapy in this population are not well described. This report details the EPILOG trial experience with unplanned coronary stent deployment and the effect of abciximab platelet glycoprotein IIb/IIIa blockade to improve clinical outcomes during 6 months of follow-up. METHODS AND RESULTS: After randomization in the EPILOG double-blind, placebo-controlled trial of abciximab therapy during percutaneous coronary intervention, 326 (12%) of 2792 patients required unplanned coronary stent deployment. Although stented patients were not distinguished by clinical variables, they had greater coronary lesion complexity by American Heart Association/American College of Cardiology criteria (P=.003) and greater incidence of lesion length >10 mm (P=.002), lesion eccentricity (P=.027), irregular lesion contour (P=.001), and bifurcation involvement (P=.019) than nonstented patients. Unplanned stents were required less often in patients treated with abciximab and low-dose, weight-adjusted heparin than in patients receiving placebo and standard-dose heparin (9.0% versus 13.7%; P=.001). Although adverse clinical outcomes including target-vessel revascularization and bleeding events were more frequent in patients requiring unplanned coronary stent deployment, abciximab therapy reduced adverse outcomes in these patients at 30 days and 6 months to a greater extent than was observed in patients not requiring stent placement. Among stented patients, abciximab therapy did not increase bleeding events. CONCLUSIONS: Patients requiring unplanned coronary stent deployment have more complex coronary lesion morphology and a more complicated clinical course after coronary intervention. Abciximab therapy both reduces the need for unplanned stent deployment and confers clinical benefit to patients requiring an unplanned stent, without increasing bleeding complications.

Abciximab↗
PubMed1998

Modifiable risk factors for vascular access site complications in the IMPACT II Trial of angioplasty with versus without eptifibatide. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

OBJECTIVES: This study was designed to identify potential predictors of vascular access site (VAS) complications in the large-scale Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II trial, which studied angioplasty with versus without a new glycoprotein (GP) IIb/IIIa receptor inhibitor (eptifibatide). BACKGROUND: GP IIb/IIIa receptor inhibition during coronary interventions has been associated with excess VAS complications. If other predictors of VAS complications could be identified, they might be manipulated to reduce complications. METHODS: A total of 4,010 patients undergoing percutaneous transluminal coronary revascularization (PTCR) were randomized into one of three bolus/20- to 24-h infusion arms: placebo bolus/placebo infusion; 135-microg/kg body weight eptifibatide bolus/0.5-microg/kg per min eptifibatide infusion; or 135-microg/kg eptifibatide bolus/0.75-microg/kg per min eptifibatide infusion. Heparin during the procedure was weight adjusted and stopped 4 h before sheaths were removed. Logistic regression modeling was used to identify independent predictors of VAS complications. RESULTS: VAS complications were more common in patients treated with eptifibatide (9.9% vs. 5.9% placebo-treated patients, p < 0.001). Multivariate analysis identified eptifibatide therapy (p < 0.0001), advanced age (p = 0.0001), longer time to sheath removal (p = 0.0002), stent placement (with intense post-stent anticoagulation) (p = 0.0004), female gender (p = 0.0006), PTCR within 24 h of thrombolytic therapy (p = 0.002), larger heparin doses during PTCR (p = 0.009), major coronary dissection (p = 0.03) and placement of a venous sheath (p = 0.04) as independent predictors of VAS complications. CONCLUSIONS: VAS complications may be reduced by early sheath removal, by avoiding placement of venous sheaths and by limiting heparin dosing to avoid excessive activated clotting times. Early sheath removal during inhibition of platelet aggregation by eptifibatide is feasible.

Aged↗
PubMed1998

The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions.

OBJECTIVES: This study sought to determine whether the duration of pretreatment with the adenosine diphosphate receptor antagonist ticlopidine prior to intracoronary stenting is associated with the incidence of procedure-related non-Q-wave myocardial infarctions (MIs). BACKGROUND: Dual antiplatelet therapy with ticlopidine and aspirin is routinely used with stenting, although ticlopidine is commonly not begun until the day of the procedure. Periprocedural MIs are at least partially platelet-dependent events. As the maximal platelet inhibitory effects of this drug take 2 to 3 days to be realized, we hypothesized that longer treatment prior to stenting would be associated with lower rates of procedure-related MIs. METHODS: We reviewed outcomes in 175 consecutive patients treated with ticlopidine prior to stenting at the Cleveland Clinic Foundation. Those patients with an elevation in creatine kinase above our laboratory normal (>210 IU/L) with > or =4% MB fraction on routine evaluation were defined as having a non-Q-wave MI. RESULTS. There were 28 patients (16%) who had a non-Q-wave MI. Longer duration of ticlopidine pretreatment was strongly associated with a lower incidence of procedure-related non-Q-wave MIs (duration of pretreatment <1 day, 29% had MI; 1 to 2 days, 14%; > or =3 days, 5%; chi-square for trend=9.6; p=0.002). Ticlopidine pretreatment of > or =3 days was associated with a significant reduction in the risk of non-Q-wave MI (unadjusted odds ratio 0.18, 95% confidence interval=0.04 to 0.78, p=0.01) compared with pretreatment of <3 days. CONCLUSIONS: Among patients undergoing intracoronary stenting, beginning ticlopidine therapy several days prior to the procedure is associated with a reduced risk of procedural non-Q-wave MIs.

Blood Vessel Prosthesis Implantation↗
PubMed1998

Glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: pathophysiologic foundation and clinical findings.

The pathophysiologic basis for potent platelet inhibition in the acute coronary syndromes has been established. In the setting of PTCA for unstable angina and non-Q-wave myocardial infarction, there are clear data for a benefit of GP IIb/IIIa inhibition, whereas for primary PTCA in evolving myocardial infarction, preliminary data are very encouraging and a large-scale clinical trial is nearly completed. Glycoprotein IIb/IIIa inhibition as an adjunct to medical therapy for unstable angina is also the subject of encouraging preliminary data, and 3 large-scale clinical trials have just been completed. Preliminary data have also been accrued for GP IIb/IIIa inhibition as conjunctive therapy with thrombolytic agents, and large clinical trials are now commencing.

Acute Disease↗
PubMed1997

Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model.

OBJECTIVES: This study sought to assess the feasibility, safety and efficacy of sustained intracoronary delivery of dexamethasone by a novel polymer-coated eluting stent. BACKGROUND: Development of techniques to provide sustained local drug delivery has focused on polymers as matrices for drug incorporation and elution. METHODS: A tantalum wire stent was coated with dexamethasone (0.8 mg) suspended in a matrix of either low (approximately 80 kD) or high (approximately 321 kD) molecular weight poly-L-lactic acid (PLLA [0.4 mg]). Uncoated stents, stents coated with PLLA or stents coated with dexamethasone in PLLA were overexpanded by 30% to the normal vessel diameter in the coronary arteries of juvenile farm pigs. Animals were euthanized 28 days later, and neointimal thicknesses were measured. Additional pigs underwent placement of stents coated with high molecular weight PLLA-dexamethasone for assessment of arterial tissue and serum concentrations of dexamethasone at 1 h and 1, 2, 10 and 28 days after stent implantation. RESULTS: In vitro dexamethasone release occurred over the first 6 days. Stents coated with low molecular weight PLLA produced an intense inflammatory neointimal response. Stents utilizing the high molecular weight PLLA were well tolerated within the coronary vessel during the 28-day experiment. However, dexamethasone did not decrease neointimal hyperplasia. Dexamethasone concentrations in the arterial tissue were approximately 300,000-fold higher than those in the serum 24 h after stent implantation, remaining approximately 3,000-fold higher at 28 days. CONCLUSIONS: The eluting stent utilizing high molecular weight PLLA appeared to be a well tolerated and effective means of providing sustained, site-specific drug delivery to the porcine coronary artery wall for at least 28 days.

Animals↗
PubMed1997

Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3 Fab) during percutaneous coronary revascularization. PROLOG Investigators.

Blockade of the platelet glycoprotein IIb/IIIa receptor by abciximab (c7E3 Fab) during coronary intervention reduces the incidence of ischemic complications, but has been associated with a doubling of the risk for bleeding complications. The present pilot study investigated whether modification of heparin dosing and/or early sheath removal would reduce the hemorrhagic complications associated with abciximab. One hundred three patients undergoing coronary intervention received abciximab (0.25 mg/kg bolus, 10 microg/min infusion for 12 hours) and aspirin and were randomized by a 2 x 2 factorial design to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. In the "standard-dose heparin" group, an initial bolus of 100 U/kg was administered to achieve a procedural activated clotting time (ACT) > or = 300 seconds; in the "low-dose heparin" group, an initial bolus of 70 U/kg was administered without adjustment for ACT. In the "late sheath removal" arm, heparin infusion was continued for the 12-hour duration of abciximab infusion, followed by sheath removal; in the "early sheath removal" group, heparin was stopped after the interventional procedure and sheaths were removed during the abciximab infusion. There were no apparent differences between patients randomized to the different treatment groups with regard to the occurrence of ischemic end points. Rates of bleeding and blood transfusion were reduced by low-dose heparin and early sheath removal and were lowest when both strategies were combined. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention may be useful in diminishing the incidence of hemorrhagic complications without loss of clinical efficacy.

Abciximab↗
PubMed1997

Quantitative evaluation of local drug delivery using the InfusaSleeve catheter.

BACKGROUND: Restenosis is the most common long-term complication after angioplasty. Local delivery of pharmacologic agents at the site of angioplasty holds promise as a means of achieving higher concentrations of drug in the arterial wall than can be obtained by systemic infusion. In this study, a novel local drug delivery catheter system, the InfusaSleeve catheter, was evaluated in a porcine coronary balloon injury model. The purpose of the study was to evaluate the efficacy of solute transfer to the arterial wall and the influence of varying supporting angioplasty balloon pressure. METHODS AND RESULTS: Ten pigs (total of 22 arterial segments) underwent overstretch balloon injury (artery/balloon ratio 1:1.29) with a standard angioplasty balloon. In 7 animals (16 arterial segments) horseradish peroxidase (HRP; 10 mg/ml) was administered locally after injury, by tracking the local infusion catheter as a sheath over the angioplasty balloon to the intended site of arterial drug delivery. Supporting angioplasty balloons were inflated to one of the three different pressures. In 3 pigs HRP (10 mg/ml) was administered intravenously. No significant arterial injury caused by the local delivery device was evident on histological examination (disruption of the internal lamina elastica, arterial media, or thrombosis). Radial concentrations of the HRP reaction product in the first 150 microns of the arterial wall were quantified against known standards by measurement of light transmission through tissue sections. Mean HRP concentrations were not significantly different from those obtained by intravenous infusion using a supporting pressure of 1 atm or a supporting pressure of 3 atm of the underlying angioplasty balloon. However, a supporting pressure of 6 atm resulted in a 6-fold greater mean HRP concentration in the arterial wall than that which could be achieved by systemic administration of an equal volume of tracer (P < 0.001). CONCLUSION: Thus solute can be delivered throughout the coronary media by the InfusaSleeve, with the magnitude of wall uptake related to support pressure. Local delivery at 6 atm support pressure produced substantially greater uptake than did systemic delivery.

Angioplasty, Balloon, Coronary↗
PubMed1997

Influence of local delivery of the protein tyrosine kinase receptor inhibitor tyrphostin-47 on smooth-muscle cell proliferation in a rat carotid balloon-injury model.

Smooth-muscle cell proliferation in response to arterial injury represents an important etiologic factor in restenosis after angioplasty. Tyrphostin-47, a protein tyrosine kinase inhibitor, inhibits smooth-muscle cell proliferation in vitro. In this study tyrphostin-47 was incorporated into matrixes to determine whether prolonged local delivery would result in a reduction of neointimal proliferation after arterial injury in a rat carotid balloon-injury model. A polymer matrix (polylactic polyglycolic acid copolymer and pluronic gel F-127, mean matrix weight 7.83 +/- 0.39 mg) was loaded with tyrphostin-47 (25% w/w). Release studies demonstrated delivery of 11% of the incorporated drug over a 21-day release period. In cell culture, tyrphostin-47 released from the polymer matrix produced a reduction in smooth-muscle cell proliferation (p < 0.0007). Balloon denudation injury of the left common carotid artery of 34 animals was performed. In 12 animals, polymer matrixes containing tyrphostin-47 were wrapped around the injured arteries to provide prolonged drug delivery (estimated dosage 28 micrograms/kg/24 hr); in 10 animals a polymer matrix without tyrphostin-47 was implanted; and in 12 animals only balloon injury was performed. The mean neointimal cross-sectional areas, luminal areas, and intima/media ratios were not significantly different among animals receiving local treatment with tyrphostin-47, sham polymer after injury, or balloon injury without polymer implantation. We conclude that despite inhibition of smooth-muscle cell proliferation by tyrphostin-47 in vitro, sustained local delivery of this tyrosine kinase inhibitor does not result in a reduction of neointimal proliferation in the rat carotid injury model.

Animals↗
PubMed1997

Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. EPIC Investigators. Evaluation of 7E3 in Preventing Ischemic Complications.

OBJECTIVES: We sought to evaluate whether patients with unstable angina undergoing coronary intervention derive particular clinical benefit from potent platelet inhibition. BACKGROUND: Plaque rupture and platelet aggregation are pathogenetic processes common to unstable angina and ischemic complications of percutaneous coronary intervention. METHODS: Of the 2,099 patients undergoing a coronary intervention in the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial, 489 were enrolled with the diagnosis of unstable angina and randomized to receive placebo, an abciximab (c7E3) bolus immediately before the intervention or an abciximab bolus followed by a 12-h infusion. The primary end point was a composite of death, myocardial infarction (MI) or urgent repeat revascularization within 30 days of randomization. The occurrence of death, MI or any revascularization within 6 months was also assessed. RESULTS: Compared with placebo, the bolus and infusion of abciximab resulted in a 62% reduction in the rate of the primary end point (12.8% vs. 4.8%, p = 0.012) among patients with unstable angina, due primarily to a reduction in the incidences of death (3.2% vs. 1.2%, p = 0.164) and MI (9% vs. 1.8%, p = 0.004). By 6 months, cumulative death and MI were further reduced by abciximab (6.6% vs. 1.8%, p = 0.018 and 11.1% vs. 2.4%, p = 0.002, respectively). The magnitude of the risk reduction with abciximab was greater among the patients with unstable angina than among other patients in the EPIC trial without unstable angina for the end points of death (interaction: p = 0.008 at 30 days, p = 0.002 at 6 months) and MI (interaction: p = 0.004 at 30 days, p = 0.003 at 6 months). CONCLUSIONS: The syndrome of unstable angina identifies patients who will experience particularly marked reductions in the risk of death and MI with abciximab during coronary intervention.

Abciximab↗
PubMed1996

Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina. A randomized multicenter trial.

BACKGROUND: Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina. METHODS AND RESULTS: Patients received intravenous heparin and standard ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin. 45 micrograms/kg bolus followed by a 0.5 microgram.kg-1. min-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 micrograms/kg bolus followed by a 1.0-microgram.kg-1, min-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24 +/- 0.11 ischemic episodes (mean +/- SEM) on Holter lasting 8.41 +/- 5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0 +/- 0.33, P < .05) and longer duration (26.2 +/- 9.8 minutes, P = .01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms. CONCLUSIONS: Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.

Adult↗
PubMed1996

Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries.

BACKGROUND: With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery. METHODS AND RESULTS: Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/ PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90 degrees of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79 +/- 0.22, 1.12 +/- 0.01, 2.36 +/- 0.60, 1.24 +/- 0.36, and 1.43 +/- 0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46 +/- 0.18 and 0.61 +/- 0.23 mm, respectively) and for the nonbiodegradable PETP (0.46 +/- 0.11 mm). CONCLUSIONS: An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.

Animals↗
PubMed1996

Local intraluminal infusion of biodegradable polymeric nanoparticles. A novel approach for prolonged drug delivery after balloon angioplasty.

BACKGROUND: Several perfusion balloon catheters are under investigation for local drug delivery; however, sustained tissue drug levels are difficult to achieve with these techniques. To overcome this problem, sustained-release, biodegradable nanoparticles represent a potential alternative for prolonged local delivery. METHODS AND RESULTS: A biodegradable polylactic-polyglycolic acid (PLGA) copolymer was used to formulate nanoparticles. Fluorescent-labeled nanoparticles were intraluminally administered in a single, 180-second infusion after balloon injury in the rat carotid model. Localization and retention at different time points and biocompatibility of nanoparticles were evaluated. To evaluate the potential of the system in the prevention of neointimal formation, dexamethasone was incorporated into the particles and delivered locally as above. Nanoparticles were seen in the three layers of the artery at 3 hours and 24 hours. At 3 days, they were mainly present in the adventitial layer, decreasing at 7 days, with no fluorescent activity at 14 days. The PLGA nanoparticles appeared to be fully biocompatible. In the dexamethasone nanoparticle study, a significant amount of dexamethasone was present in the treated segment for up to 14 days after a single infusion, with no plasma levels detected after the first 3 hours. There was a 31% reduction in intima-media ratio in animals treated with local dexamethasone nanoparticles compared with control. CONCLUSIONS: Nanoparticles successfully penetrated into the vessel wall and persisted for up to 14 days after a short, single intraluminal infusion. Local administration of nanoparticles with incorporated dexamethasone significantly decreased neointimal formation. This methodology appears to have important potential for clinical applications in local drug delivery.

Angioplasty, Balloon, Coronary↗
PubMed1996

Anthracycline-induced cardiotoxicity.

PURPOSE: To review the current understanding of the clinical significance, detection, pathogenesis, and prevention of anthracycline-induced cardiotoxicity. DATA SOURCES: A MEDLINE search of the English-language medical literature and a manual search of the bibliographies of relevant articles, including abstracts from national cardiology meetings. STUDY SELECTION: Pertinent clinical and experimental studies addressing the clinical relevance, pathogenesis, detection, and prevention of anthracycline cardiotoxicity were selected from peer-reviewed journals without judgments about study design. A total of 137 original studies and 9 other articles were chosen. DATA EXTRACTION: Data quality and validity were assessed by each author independently. Statistical analysis of combined data was inappropriate given the differences in patient selection, testing, and follow-up in the available studies. DATA SYNTHESIS: Anthracycline-induced cardiotoxicity limits effective cancer chemotherapy by causing early cardiomyopathy, and it can produce late-onset ventricular dysfunction years after treatment has ceased. Detection of subclinical anthracycline-induced cardiomyopathy through resting left ventricular ejection fraction or echocardiographic fractional shortening is suboptimal. Conventional doses of anthracycline often lead to permanent myocardial damage and reduced functional reserve. Underlying pathogenetic mechanisms may include free-radical-mediated myocyte damage, adrenergic dysfunction, intracellular calcium overload, and the release of cardiotoxic cytokines. Dexrazoxane is the only cardioprotectant clinically approved for use against anthracyclines, and it was only recently introduced for selected patients with breast cancer who are receiving anthracycline therapy. CONCLUSIONS: A rapidly growing number of persons, including an alarming fraction of the 150 000 or more adults in the United States who have survived childhood cancer, will have substantial morbidity and mortality because of anthracycline-related cardiac disease. The development of effective protection against anthracycline-induced cardiotoxicity will probably have a significant effect on the overall survival of these patients.

Acute Disease↗
PubMed1996

Restenosis--an open file.

The main procedural drawback to percutaneous coronary angioplasty is restenosis of the treated site within 6 months. Despite advances in equipment, technique, and adjunctive therapies, restenosis has occurred in approximately one-third to one-half of all patients. The biology of restenosis can be divided into plaque persistence and recoil, thrombus formation and transformation, and cellular proliferation and vascular remodeling. Animal models of restenosis have helped to elucidate these mechanisms of restenosis and provide a means to test pharmacologic and mechanical strategies to reduce stenosis recurrence. While numerous agents have been tested in animal models, until recently none has translated into benefit in large-scale clinical trials. Two therapeutic "hopefuls" which have recently emerged in clinical practice are the potent platelet inhibitors, glycoprotein IIb/IIIa receptor antagonists, and intracoronary metallic stents. The IIb/IIIa receptor antagonists target thrombus formation at the angioplasty site, thereby minimizing abrupt vessel closure acutely and neointimal growth chronically, while intracoronary stents safely produce a large coronary arterial lumen acutely and prevent vessel recoil. Separately, these therapeutic strategies have been shown to reduce clinical restenosis 20-30% at 6-month follow-up. With these encouraging results, the future will certainly provide more pharmacologic and mechanical therapies targeting restenosis. With increased understanding of the restenotic process and continued refinement of effective treatments, it may be possible one day to prevent stenosis recurrence.

Angioplasty, Balloon, Coronary↗
PubMed1995

Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention.

We studied the pharmacokinetic and pharmacodynamic properties of integrelin, a novel platelet glycoprotein IIb/IIIa receptor inhibitor, in patients undergoing elective percutaneous coronary intervention. Patients were randomized to placebo (n = 19) or to 1 of 4 integrelin dosing regimens (total n = 54) that were studied sequentially. All patients received aspirin and heparin. Patients were followed until discharge for the occurrence of adverse clinical events: death, myocardial infarction, coronary artery bypass surgery, repeat intervention, or recurrent ischemia. Bleeding was the primary safety end point. Frequent blood sampling was performed for adenosine diphosphate-induced platelet aggregations. Simplate bleeding times were performed. Adverse clinical events occurred less often in the integrelin-treated patients, although the overall numbers were too small to make a definitive statement as to clinical efficacy. There was no significant increase in serious bleeding among integrelin-treated patients. The 2 highest integrelin boluses (180 and 135 micrograms/kg) immediately (15 minutes after the bolus) provided > 80% inhibition of adenosine diphosphate-induced platelet aggregation in > 75% of treated patients. A constant integrelin infusion of 0.75 micrograms/kg/min maintained this marked antiplatelet effect, whereas an infusion of 0.50 micrograms/kg/min allowed gradual recovery of platelet function. Elective coronary intervention was performed safely and with no significant increase in serious bleeding events using integrelin with aspirin and heparin as an antithrombotic regimen. Integrelin provided rapid, intense, and persistent ex vivo platelet inhibition during coronary intervention. This new antiplatelet agent may be beneficial in reducing platelet-mediated ischemic complications of percutaneous coronary intervention.

Aged↗
PubMed1995

Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model.

BACKGROUND: The relation among the coagulation cascade, its individual proteins, and the response to vascular injury is largely undefined. We have evaluated the effect of four probes that block specific levels of coagulation cascade on neointimal hyperplasia in the atherosclerotic rabbit arterial injury model. METHODS AND RESULTS: Focal femoral atherosclerosis was induced by air-desiccation injury and hypercholesterolemic diet in 48 New Zealand White rabbits, followed by balloon angioplasty. Active-site inactivated factor VIIa (DEGR-VIIa), which blocks the binding of factor VIIa to tissue factor, was administered (n = 12 arteries) by intravenous bolus (1 mg/kg) at the time of balloon angioplasty and followed by infusion of 50 micrograms.kg-1.h-1 for 3 days; for the control (n = 13 arteries), 150 U heparin was injected as bolus and followed by infusion of saline at 50 microL.kg-1.min-1. Recombinant tissue factor pathway inhibitor (TFPI), which binds factor Xa and inhibits the tissue factor-factor VIIa complex and factor Xa, was given as a 1 mg/kg bolus followed by 15 micrograms.kg-1.min-1 infusion for 3 days (n = 17 arteries). Recombinant tick anticoagulant peptide (TAP; n = 15 arteries) and hirudin (n = 14 arteries), which block factor Xa and thrombin, respectively, were administered as a 1 mg/kg bolus followed by 5 micrograms.kg-1.min-1 infusion for 3 days. These three groups had their own controls (n = 14 arteries). There were no differences among treatment groups in preangioplasty and postangioplasty minimal luminal diameter (MLD) by angiography. The mean MLD 21 days after balloon angioplasty was significantly different between control and DEGR-VIIa-treated groups (0.74 +/- 0.25 and 1.24 +/- 0.27 mm, respectively; P = .0001) and between the TFPI-treated group and others (0.88 +/- 0.21 mm for control, 0.97 +/- 0.22 mm for hirudin-treated, 0.98 +/- 0.14 mm for TAP-treated, and 1.32 +/- 0.21 mm for TFPI-treated arteries; P = .0001 by ANOVA). By quantitative histological analysis, the ratio of neointimal cross-sectional area compared with the area of internal elastic lamina in the DEGR-VIIa-treated group was significantly less than control (0.48 +/- 0.12 versus 0.67 +/- 0.12, P = .0001), and the ratio of neointimal cross-sectional area to the area demarcated by the internal elastic lamina of the TFPI-treated group was significantly reduced compared with the other groups (0.46 +/- 0.20 for TFPI-treated, 0.67 +/- 0.15 for hirudin-treated, 0.61 +/- 0.15 for TAP-treated, and 0.64 +/- 0.13 for control groups; P = .003). CONCLUSIONS: Treatment with DEGR-VIIa or TFPI for 3 days in this rabbit atherosclerotic injury model reduced angiographic restenosis and decreased neointimal hyperplasia compared with controls. These findings highlight the importance of early initiators of the extrinsic coagulation pathway, especially factor VII and tissue factor, in the response to arterial injury.

Angioplasty, Balloon↗