Effects of abciximab, ticlopidine, and combined Abciximab/Ticlopidine therapy on platelet and leukocyte function in patients undergoing coronary angioplasty.

BACKGROUND: Abciximab and ticlopidine reduce adverse cardiovascular events after percutaneous transluminal coronary angioplasty (PTCA). The goal of the current study was to determine if combined abciximab/ticlopidine therapy inhibits arterial thrombosis more effectively than either treatment alone. The effect of each therapy on platelet-leukocyte interactions was also investigated. METHODS AND RESULTS: Whole blood samples from 14 patients undergoing PTCA who received abciximab therapy, ticlopidine therapy, or both treatments were evaluated using dynamic experimental systems. Mural thrombus formation under arterial shear conditions (1500 s(-1)) was determined in a parallel plate flow chamber. Shear-induced platelet aggregation was evaluated using a cone-and-plate viscometer at a shear rate of 3000 s(-1). Of the 3 treatments, combined abciximab/ticlopidine therapy produced the most consistent reduction in shear-induced platelet aggregation and the most prolonged inhibition of mural thrombosis. Three days after PTCA, abciximab/ticlopidine treatment decreased mural thrombus formation to approximately 50% of baseline values. Abciximab treatment alone inhibited mural thrombosis for only 1 day after PTCA, whereas ticlopidine treatment alone had no significant effect. Two hours after PTCA, abciximab therapy significantly decreased the number of circulating platelet-neutrophil aggregates but significantly enhanced P-selectin-mediated leukocyte adhesion on the collagen/von Willebrand factor-platelet surface. CONCLUSIONS: Combined therapy with abciximab and ticlopidine has a prolonged inhibitory effect on mural thrombosis formation relative to either treatment alone. Further, we demonstrated an unexpected effect of abciximab in enhancing P-selectin-mediated leukocyte adhesion.

Abciximab readministration: results of the ReoPro Readministration Registry.

BACKGROUND: Platelet glycoprotein IIb/IIIa blockade with abciximab (ReoPro) improves the clinical outcomes of percutaneous coronary intervention. This registry was conducted to characterize the effects of repeated administration of abciximab during intervention. METHODS AND RESULTS: We recruited 500 consecutive patients at 22 centers in the United States who were receiving abciximab for at least a second time during percutaneous coronary intervention. Safety was measured as the incidence of hypersensitivity reactions, major bleeding, and thrombocytopenia. Efficacy was assessed as event-free clinical success. Human antichimeric antibody (HACA) responses were also characterized. There were no cases of hypersensitivity (95% upper confidence bound, 0.3%), major bleeding, or death. Clinical success was 94.4%. Thrombocytopenia occurred in 23 patients (4.6%; 95% CI, 2.8% to 6.4%), including 12 (2.4%; 95% CI, 1.1% to 3.7%) who developed profound thrombocytopenia (<20x10(9) cells/L). In 2 patients (0.4%), profound thrombocytopenia did not develop until after hospital discharge; in 4 (0.8%), profound thrombocytopenia recurred despite platelet transfusion. Before a first readministration, a positive HACA titer was present in 22 of 454 patients (4.8%); after a first readministration, an additional 82 of 432 (19.0%) became HACA-positive. HACA did not neutralize the in vitro inhibition of platelet aggregation by abciximab or correlate with clinical events. CONCLUSIONS: The results, including overall rates of thrombocytopenia, were consistent with randomized clinical trials of first abciximab treatment. However, there was a shift from mild to profound thrombocytopenia, and cases of delayed presentation and of recurrent thrombocytopenia were seen. These findings suggest that indications and guidelines for first-time use apply to retreatment, particularly the systematic monitoring for thrombocytopenia.

Hemodynamic vascular forces contribute to impaired endothelium-dependent vasodilation in reperfused canine epicardial coronary arteries.

OBJECTIVES: We studied canine coronary arterial vasoreactivity after occlusion and reperfusion to examine whether reduced flow or pressure contributed to the abnormalities observed. BACKGROUND: Ischemia and reperfusion alter endothelial and myocardial function. Causative factors may include altered flow, complement activation or free radical production by endothelial or white blood cells after reoxygenation and neutrophil activation. METHODS: The coronary arteries of anesthetized, open chest dogs were subjected to 90-min occlusion +/- 2 h of reperfusion. The effect of reperfusion on arterial responses to intracoronary acetylcholine, nitroprusside and phenylephrine was studied using in vivo ultrasound. Arterial segments were also harvested, perfused ex vivo with cell-free buffer and exposed to potassium chloride, nitroprusside, acetylcholine and bradykinin. The effect of ex vivo flow cessation with or without maintained intralumen pressure was also studied. RESULTS: Results are expressed as mean value +/- SEM. In vivo arterial cross-sectional area increased during infusion with acetylcholine (10(-5) mol/liter [18.5 +/- 9%]) and nitroprusside (10(-5) mol/liter [22.5 +/- 10%]) and decreased with phenylephrine (10(-5) mol/liter [7.6 +/- 7%]). After reperfusion, acetylcholine caused 13.5 +/- 9% vasoconstriction. Nitroprusside and phenylephrine responses were unchanged. Reperfused arterial segments also showed impaired vasodilation in response to 10(-6) mol/liter of acetylcholine (10.6 +/- 5.1% vs. 47.1 +/- 4.9% in control vessels) and 10(-8) mol/liter of bradykinin (4.4 +/- 6.7% vs. 27.9 +/- 8% in control vessels). Ex vivo flow cessation impaired acetylcholine-mediated vasodilation, but this abnormality was prevented when high intralumen pressure was maintained during the no-flow period. CONCLUSIONS: Reduction in flow and intralumen pressure contribute to the impaired acetylcholine-mediated vasodilation seen after coronary occlusion. This is prevented by maintaining high intralumen pressure during the no-flow period, suggesting that hemodynamic forces may change endothelial function independent of circulating complement or blood cell elements.

Transient atrial dysfunction after conversion of chronic atrial fibrillation to sinus rhythm.

Although conversion of atrial fibrillation (AF) to sinus rhythm can usually be accomplished by electrical or drug therapy, effective atrial systole may not be restored. To investigate the return of atrial transport function and its relation to the duration of the arrhythmia, Doppler echocardiography was performed after conversion in 18 patients with acute AF (less than or equal to 1 week duration), 14 patients with chronic AF (greater than 1 week duration) and 15 control patients. Flow velocities during rapid filling (E wave) and atrial systole (A wave) were measured in both left and right ventricles. Patients in the acute AF group had left ventricular A waves (49 +/- 4 cm/s) and A/E ratios (0.97 +/- 0.1) similar to those of the control patients (55 +/- 7 cm/s, 0.87 +/- 0.08, respectively). In contrast, patients in the chronic AF group had much smaller A waves (19 +/- 5 cm/s) and A/E ratios (0.30 +/- 0.08) than those in the other 2 groups (p less than 0.001). Five patients with chronic AF (36%) had complete left atrial paralysis (A/E = 0) despite normal sinus P waves. Measurements in the right ventricle showed similar differences among the groups. Patients with chronic AF who maintained sinus rhythm showed an increase in A/E ratio to control levels, from 0.45 +/- 0.1 to 0.93 +/- 0.1 (p = 0.003) at 48 days (average) after conversion. Thus, atrial transport function is normal after brief periods of AF, but reduced or absent when conversion is achieved after the arrhythmia has been sustained greater than 1 week.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of abciximab on the pattern of reperfusion in patients with acute myocardial infarction treated with primary angioplasty. RAPPORT investigators. ReoPro And Primary PTCA Organization and Randomized Trial.

We investigated the effect of platelet fibrinogen receptor blockade on infarct size after primary angioplasty. Abciximab significantly reduced the time-to-peak creatine kinase without affecting enzymatic infarct size, suggesting a beneficial effect on the pattern and speed of reperfusion.

Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials. Improve Long-term Outcome with abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibition in STENTing.

BACKGROUND: Abciximab during percutaneous coronary revascularization reduces ischemic complications, but concern exists regarding increased bleeding risk should emergency coronary surgical procedures be required. METHODS: Outcomes were assessed among 85 patients who required coronary artery bypass grafting operations after coronary intervention in two randomized placebo-controlled trials of abciximab. Comparisons were made between patients in the pooled placebo and abciximab groups. RESULTS: The incidence of coronary surgical procedures was 2.17% and 1.28% among patients randomized to placebo and abciximab, respectively (p = 0.021). Platelet transfusions were administered to 32% and 52% of patients in the placebo and abciximab groups, respectively (p = 0.059). Rates of major blood loss were 79% and 88% in the placebo and abciximab groups, respectively (p = 0.27); transfusions of packed red blood cells or whole blood were administered in 74% and 80% of patients, respectively (p = 0.53). Surgical reexploration for bleeding was required in 3% and 12% of patients, respectively. Death and myocardial infarction tended to occur less frequently among patients who had received abciximab. CONCLUSIONS: Urgent coronary artery bypass grafting operations can be performed without an incremental increase in major hemorrhagic risk among patients on abciximab therapy.

Platelet glycoprotein IIb/IIIa receptor antagonists and their use in elderly patients.

With increasing age of the general population, cardiovascular diseases are becoming a greater health burden. Coronary artery disease remains a major cause of morbidity and mortality worldwide. Among the various pathophysiological processes, platelets play a pre-eminent role. With the identification of the glycoprotein (GP) IIb/IIIa receptor as the final common pathway for platelet aggregation, potent antiplatelet agents have been developed. These GP IIb/IIIa antagonists have been shown to be effective in improving outcomes among patients undergoing percutaneous coronary interventions and for the treatment of acute coronary syndromes. By pooling the results of several large-scale trials, these benefits have been found to extend to the elderly population. Among 7860 patients undergoing percutaneous coronary intervention, the occurrence of death or myocardial infarction at 30 days was reduced from 10.0 to 5.9% (odds ratio 0.56; 95% confidence level, 0.37 to 0.83) with abciximab compared with placebo, in those >70 years of age. Importantly, this benefit was achieved without an increase in major bleeding complications. Similarly favourable trends were also observed among elderly patients treated with tirofiban or eptifibatide for acute coronary syndromes. As such, GP IIb/IIIa antagonists are effective in preventing ischaemic complications and can be safely administered to elderly patients.

Effects of resistive training on left ventricular function.

Although several studies have evaluated the effects of endurance training on left ventricular (LV) function, few studies have looked at resistive training effects. Acute isometric exercise increases blood pressure and has little effect on LV function, causing only mild increases in ejection fraction and stroke volume index. However, acute isometric exercise does increase LV diastolic diameter to a lesser extent than dynamic exercise. Most studies of resistive training on LV function have been cross-sectional or short term (10 to 12 wk) training studies on athletes and suggest that increases in LV wall thickness and mass are dependent upon the intensity and duration of training. Most resistive training studies show no increase in left ventricular volume, as can be seen in endurance trained athletes. Despite the increase in LV mass with resistive training, indices of LV systolic and diastolic function do not change. In hypertensive and cardiac patients with normal LV function at rest, resistive training increases LV mass index without deleterious effects on LV systolic and diastolic function. However, in patients with abnormal resting LV function, resistive training can have adverse effects on LV systolic function. Overall, moderate levels of resistive training can be a useful adjunct to cardiac rehabilitation programs, with the caveat that it be used with caution in patients with abnormal LV function at rest.

Effects of diltiazem or propranolol during exercise training of hypertensive men.

This was a prospective, randomized, double-blind, placebo-controlled trial to establish whether beta blockers or calcium-channel blockers limit exercise capacity and training responses in men with mild hypertension. Circuit weight and aerobic training was used to assess the effects of drugs on cardiovascular fitness and muscle strength. Fifty-two sedentary men, ages 25-59 yr, with a diastolic blood pressure of 90-105 mm Hg off drugs, without significant ST depression during maximal stress testing, received diltiazem, propranolol, or placebo. Maximal oxygen uptake (VO2max) and exercise duration during treadmill testing, as well as one-repetition maximal strength, were assessed on eight weight machines after a single-blind placebo baseline, after 2 wk of drug run-in, and after 10 wk of exercise training. Total daily doses were 240 mg for propranolol and 360 mg for diltiazem. Propranolol decreased VO2max after drug run-in (P less than 0.05). Exercise training increased VO2max (P less than 0.05) in the diltiazem and placebo groups. After training VO2max in the propranolol group increased (P less than 0.05) from run-in but not beyond baseline levels. Thus, the reduction of VO2max consequent to propranolol therapy limited the overall benefits of training. Exercise duration did not change with run-in and increased (P less than 0.05) with training by 22%, 19%, and 10% for the diltiazem, placebo, and propranolol groups, respectively. Strength after run-in was unchanged, and exercise training increased strength (P less than 0.0001) on all weight machines in all groups. The results show an advantage of diltiazem to propranolol, particularly among physically active patients engaged in aerobic exercise who require antihypertensive therapy.

Transferring from clopidogrel loading dose to prasugrel loading dose in acute coronary syndrome patients. High on-treatment platelet reactivity analysis of the TRIPLET trial.

High on-treatment platelet reactivity (HPR) has been identified as an independent risk factor for ischaemic events. The randomised, double-blind, TRIPLET trial included a pre-defined comparison of HPR in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) following a placebo/600-mg clopidogrel loading dose (LD) immediately before a subsequent prasugrel 60-mg or 30-mg LD. Platelet reactivity was assessed using the VerifyNow® P2Y12 assay (P2Y12 Reaction Units, PRU) within 24 hours (h) following the placebo/clopidogrel LD (immediately prior to prasugrel LD), and at 2, 6, 24, 72 h following prasugrel LDs. The impact of CYP2C19 predicted metaboliser phenotype (extensive metabolisers [EM] and reduced metabolisers [RM]) on HPR status was also assessed. HPR (PRU ≥240) following the clopidogrel LD (prior to the prasugrel LD) was 58.5% in the combined clopidogrel LD groups. No significant difference was noted when stratified by time between the clopidogrel and prasugrel LDs (≤6 hs vs>6 h). At 6 h following the 2nd loading dose in the combined prasugrel LD groups, HPR was 7.1%, with 0% HPR by 72 h. There was no significant effect of CYP2C19 genotype on pharmacodynamic (PD) response following either prasugrel LD treatments at any time point, regardless of whether it was preceded by a clopidogrel 600-mg LD. In conclusion, in this study, patients with ACS intended for PCI showed a high prevalence of HPR after clopidogrel 600-mg LD regardless of metaboliser status. When prasugrel LD was added, HPR decreased substantially by 6 h, and was not seen by 72 h.

Thrombolytic therapy for acute myocardial infarction in the 1990s.

The efficacy of intravenous thrombolytic agents in preserving left ventricular function and in decreasing mortality from an acute myocardial infarction was demonstrated in the 1980s. The 1990s will concentrate on adjunctive therapy to thrombolysis in the treatment of an acute myocardial infarction.

Exercise training combined with antihypertensive drug therapy. Effects on lipids, blood pressure, and left ventricular mass.

We studied exercise training combined with the use of antihypertensive drugs and examined the following questions. (1) Are there additive antihypertensive benefits with exercise and drug therapy combined? (2) Does drug therapy limit exercise-induced lipid improvements? (3) Does exercise that includes weight training and walking/jogging affect the left ventricle? Fifty-two hypertensive men were randomly assigned, double-blind, to diltiazem hydrochloride, sustained release (360 mg daily), propranolol hydrochloride (240 mg daily), or placebo and exercised three times per week for 10 weeks. Baseline blood pressure (145/97 mm Hg) fell after training (131/84 mm Hg) in all groups. Exercise decreased total and low-density lipoprotein cholesterol levels in all groups. Increases in the levels of high-density lipoprotein cholesterol were similar in placebo and diltiazem groups, whereas the propranolol group changed in an opposite direction. In all groups, left ventricular mass increased with training, while diastolic function was unchanged. We conclude that (1) drug therapy provided no additive benefit to the antihypertensive effects of exercise, (2) propranolol limited improvements in high-density lipoprotein cholesterol, and (3) exercise did not adversely affect the left ventricle.

Effect of tris(hydroxymethyl)aminomethane on ischemic myocardium.

Intracellular acidosis may depress myocardial function and metabolism during ischemia. In the present study, the function and metabolism of a globally ischemic, isovolumic cat left ventricle preparation, perfused with oxygenated Krebs-Ringer biocarbonate solution, was examined. Addition of tris(hydroxymethyl)-aminomethane (Tris) (15 mM) to the perfusate at physiologic pH and PCO2 increased performance during ischemia to a greater extent and for a longer period than low PCO2 )15 mmHg), alkalotic (pH, 7.8) perfusate and a control sucrose perfusate. Under nonischemic conditions the inotropic effect of Tris was only briefly greater than sucrose perfusate. The inotropic effect of Tris during ischemia did not appear to depend on changes in coronary flow, oxygen consumption, sodium concentration, perfusate osmolality, or catecholamine release. During ischemia, lactate production was unchanged with Tris, but increased with low PCO2-alkalosis. Tissue levels of ATP and creatine phosphate for control ischemic hearts did not differ from Tris-perfused or low PCO2-alkalosis hearts. Thus, Tris appears to exert an inotropic effect that is more prominent in ischemic than nonischemic myocardium. The results are consistent with the possibility that Tris acts as an intracellular buffer to increase the efficiency of energy production and/or utilization during ischemia.

Changes in myosin isoenzymes, ATPase activity, and contraction duration in rat cardiac muscle with aging can be modulated by thyroxine.

To determine whether the relative decline in cardiac myosin isoenzyme V1 with maturation continues progressively into senescence and whether thyroxine could reverse age-associated changes in the myosin isoenzyme profile and contraction, rats 2, 8, and 24 months old were treated with thyroxine, 6.4 mg/kg, for 7 days. Myosin isoenzymes, Ca2+-myosin ATPase activities, and isometric contractile function were measured in cardiac preparations from thyroxine-treated animals and age-matched controls. Right ventricular hypertrophy did not occur with aging in controls. Thyroxine increased right ventricular weight in each age group compared to the control group. Body weight decreased by 10% in all thyroxine-treated rats. The relative right ventricular V1 isoenzyme content progressively decreased from 75 +/- 1% to 54 +/- 1% and 14 +/- 1% in controls at 2, 8, and 24 months, respectively, and was associated with a reciprocal increase in V3 myosin isoenzyme. Ca2+-myosin ATPase activity also progressively declined monotonically with age in the control rats from 854 +/- 28 nmol Pi/mg prot/min at 2 months to 529 +/- 28 nmol Pi/mg prot/min at 24 months. Thyroxine administration increased right ventricular V1 at each age to 97 +/- 2%, 73 +/- 2%, and 59 +/- 2% at 2, 8, and 24 months, respectively. A thyroxine induced increase in the Ca2+-myosin ATPase activity could be detected only in the 24-month-old animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Elastic properties of the human chest during cardiopulmonary resuscitation.

Sternal displacement during CPR was measured in 11 adults and 2 manikins (Recording Resusci Anne) while the chest was compressed with variable maximum pulse compression force at a rate of 60/min with compression duration of 0.5-0.6 sec. In 10 patients, the pulsatile sternal elastic characteristic can be satisfactorily described with a 2nd degree polynomial F = beta Ds + gamma D2s, where beta = 54.9 +/- 29.4 (mean +/- SD) N/cm is the pulsatile initial elasticity and gamma = 10.8 +/- 4.1 N/cm2 is the posterior resiliency. The sternal characteristics of manikins were linear F = kDs with high elasticity constants, k = 131 and 142 N/cm. Therefore, the manikins tested differ significantly in elasticity characteristics from the human chest during resuscitation. In general, the manikin: (1) has markedly greater stiffness at the onset of compression, and (2) maintains a linear stiffness throughout the usual range of displacement, rather than becoming stiffer with greater chest displacement.

Abciximab, ticlopidine, and concomitant abciximab-ticlopidine therapy: ex vivo platelet aggregation inhibition profiles in patients undergoing percutaneous coronary interventions.

BACKGROUND: We examined the ex vivo platelet aggregation profiles of patients who underwent percutaneous coronary intervention and received either abciximab, ticlopidine, or both agents. STUDY DESIGN AND METHODS: The trial was a prospective, nonrandomized, single-center, open-label study of 42 patients undergoing percutaneous coronary intervention who received the following regimens: group 1, abciximab (0.25 mg/kg bolus and 12-hour, 0.125 microg/kg per minute infusion); group 2, ticlopidine (250 mg twice daily for 14 consecutive days, initiated 12 to 18 hours before intervention); group 3, abciximab plus ticlopidine initiated 12 to 18 hours before procedure; and group 4, abciximab plus ticlopidine initiated 72 to 96 hours before procedure. Platelet aggregation measurements to adenosine diphosphate (ADP) and a thrombin receptor activating peptide (TRAP, 8 micromol/L) were obtained before ticlopidine treatment, after initiation of ticlopidine, and immediately before abciximab treatment and intervention, then at several time periods after onset of abciximab treatment. Platelet surface abciximab levels were monitored by flow cytometry. RESULTS: Neither ticlopidine regimen resulted in appreciable platelet inhibition before intervention and before administration of abciximab. In the ticlopidine-only arm, suppression of platelet aggregation to the weakest stimuli (5 micromol/L ADP; 23% +/- 7.5%) was detected within 24 hours after intervention, with maximal inhibition to both 5 and 20 micromol/L ADP observed 7 days after intervention (48% +/- 7.9% and 18% +/- 8.7%, respectively). In contrast, ticlopidine marginally suppressed TRAP-mediated platelet activation at times when maximal effects on ADP-mediated platelet aggregation were evident. Neither ticlopidine regimen appreciably enhanced platelet inhibition during or shortly after cessation of abciximab treatment. For all 3 abciximab treatment arms, profound inhibition of ADP-induced (>80%) and TRAP-induced (>65%) platelet aggregation was observed 2 hours after treatment. In the abciximab-only arm, platelet aggregation responses gradually recovered, with the rate of response directly proportional to the strength of stimuli. However, in the ticlopidine plus abciximab arms, recovery of platelet aggregation at later times (7 and 14 days) reached a plateau and reflected the extent of inhibition observed in ticlopidine-treated patients. No difference in the clearance of surface-bound abciximab from circulating platelets was observed between the abciximab and abciximab plus ticlopidine arms. CONCLUSIONS: Concomitant abciximab plus ticlopidine treatment yields a platelet inhibition profile that is a composite of the effects of the 2 agents. In the early stages of treatment, inhibition of ex vivo platelet aggregation was mediated primarily by abciximab; effects were more moderate and were predominately mediated by ticlopidine.

Effect of glycoprotein IIb/IIIa inhibition without thrombolytic therapy on reperfusion in acute myocardial infarction: results of ReoMI pilot study.

The efficacy of abciximab and moderate dose heparin in attaining reperfusion in acute MI was tested in a multicenter pilot study. Patients with acute MI of less than 6-hr onset triaged to primary PTCA received intravenous abciximab bolus and infusion and heparin (70 u/kg) in the emergency room. Mean time to angiography from administration of abciximab was 34 +/- 23 min. TIMI flow rates were: grade 0-62%, grade I-20%, grade II-9%, and grade III-9%. Primary PTCA was performed with 100% success rate. Access site bleeding occurred in 10% of patients with no incidence of intracranial bleeding. TIMI II/III flow rates were 50% in a patient subset where angiography was delayed by 45 min. While not an alternative to thrombolytics in AMI, abciximab administration in the emergency room in patients triaged to PTCA may be beneficial in situation where door to needle time is delayed as TIMI II/III flows may be attained in some patients. Cathet. Cardiovasc. Intervent. 48:430-434, 1999.

Readministration of abciximab: interim report of the ReoPro readministration registry.

Even with continued improvements in the technology of percutaneous coronary intervention (PCI), approximately 10% to 20% of patients undergoing PCI will require repeat procedures within 1 year. Furthermore, because of the chronic nature of coronary artery disease, many patients will require additional treatment with PCI well after an initial episode of care. Abciximab (ReoPro), a chimeric (murine/human) monoclonal antibody fragment (c7E3 Fab), has been shown to significantly improve periprocedural and long-term outcomes associated with PCI and to reduce the need for repeat target vessel revascularization. However, because the structure of abciximab is derived from an antibody, concern has been raised about subsequent repeat administration. To prospectively evaluate the safety and efficacy of abciximab readministration, we established the ReoPro Readministration Registry with the intent to determine the efficacy, human antichimeric antibody response and rates of thrombocytopenia, bleeding, intracranial hemorrhage, and anaphylaxis in at least 500 patients being retreated with abciximab. The study was conducted at 19 centers beginning in March 1997. This article details interim data that are based on the first 329 patients. Data to date indicate that readministration with abciximab is safe and efficacious and that the same indications for first-time use should apply to subsequent readministration.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators.

BACKGROUND: The benefit of catheter-based reperfusion for acute myocardial infarction (MI) is limited by a 5% to 15% incidence of in-hospital major ischemic events, usually caused by infarct artery reocclusion, and a 20% to 40% need for repeat percutaneous or surgical revascularization. Platelets play a key role in the process of early infarct artery reocclusion, but inhibition of aggregation via the glycoprotein IIb/IIIa receptor has not been prospectively evaluated in the setting of acute MI. METHODS AND RESULTS: Patients with acute MI of <12 hours' duration were randomized, on a double-blind basis, to placebo or abciximab if they were deemed candidates for primary PTCA. The primary efficacy end point was death, reinfarction, or any (urgent or elective) target vessel revascularization (TVR) at 6 months by intention-to-treat (ITT) analysis. Other key prespecified end points were early (7 and 30 days) death, reinfarction, or urgent TVR. The baseline clinical and angiographic variables of the 483 (242 placebo and 241 abciximab) patients were balanced. There was no difference in the incidence of the primary 6-month end point (ITT analysis) in the 2 groups (28.1% and 28.2%, P=0.97, of the placebo and abciximab patients, respectively). However, abciximab significantly reduced the incidence of death, reinfarction, or urgent TVR at all time points assessed (9.9% versus 3.3%, P=0.003, at 7 days; 11.2% versus 5.8%, P=0.03, at 30 days; and 17.8% versus 11.6%, P=0.05, at 6 months). Analysis by actual treatment with PTCA and study drug demonstrated a considerable effect of abciximab with respect to death or reinfarction: 4.7% versus 1.4%, P=0.047, at 7 days; 5.8% versus 3.2%, P=0.20, at 30 days; and 12.0% versus 6.9%, P=0.07, at 6 months. The need for unplanned, "bail-out" stenting was reduced by 42% in the abciximab group (20.4% versus 11.9%, P=0.008). Major bleeding occurred significantly more frequently in the abciximab group (16.6% versus 9.5%, P=0.02), mostly at the arterial access site. There was no intracranial hemorrhage in either group. CONCLUSIONS: Aggressive platelet inhibition with abciximab during primary PTCA for acute MI yielded a substantial reduction in the acute (30-day) phase for death, reinfarction, and urgent target vessel revascularization. However, the bleeding rates were excessive, and the 6-month primary end point, which included elective revascularization, was not favorably affected.