Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease.

BACKGROUND: Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease. METHODS AND RESULTS: Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%. CONCLUSIONS: -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Thrombolytic therapy for women with myocardial infarction: is there a gender gap? Thrombolysis and Angioplasty in Myocardial Infarction Study Group.

OBJECTIVES: The goal of this study was to investigate whether female gender portends an adverse prognosis independent of the severity of the underlying disease after acute myocardial infarction treated by thrombolysis. A total of 348 women were compared with 1,271 men enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trials. BACKGROUND: The reasons for gender differences in the management and prognosis of acute coronary artery syndromes remain poorly defined. The extent to which gender itself explains observed differences in outcome and use of diagnostic procedures remains unclear because confounding factors have not been specified. METHODS: Patients < 76 years of age presenting within 6 h of onset of ischemic symptoms with electrocardiographic ST segment elevation and without contraindications to thrombolysis, previous infarction in the same distribution or cardiogenic shock were prospectively enrolled in Phases 1 to 3, 5 and 7 of the TAMI trials. All patients received recombinant tissue-type plasminogen activator, urokinase or a combination of both agents. Protocol-mandated cardiac catheterization was performed during the hospital period. Rescue coronary angioplasty was carried out for reperfusion failure at angiography 90 min after initiation of thrombolytic therapy. Coronary artery bypass grafting or coronary angioplasty was performed for clinical indications. RESULTS: Women were older than men (61.0 +/- 9.7 vs. 55.8 +/- 10.1 years, mean +/- SD) and had a higher incidence of many risk factors for adverse outcome after myocardial infarction. There were no differences in baseline hemodynamic variables or time to thrombolytic treatment. Rates of acute and predischarge infarct-related artery patency and global and regional left ventricular function were similar in the two groups. Rates of in-hospital coronary angioplasty (52.6% and 54.1%) and bypass graft surgery (20.4% and 22.0%) were comparable in women and men, respectively. Women had higher unadjusted rates of mortality (9.2% vs. 5.4%, p = 0.014), reinfarction (6.4% vs. 2.6%, p = 0.005) and hemorrhagic stroke (2.0% vs. 0.55%, p = 0.017) than did men during the hospital period. When adjusted for clinical and angiographic variables, differences in mortality and hemorrhagic stroke did not reach statistical significance, and the risk of reinfarction was only marginally associated with gender. CONCLUSIONS: In selected patients undergoing thrombolytic therapy and cardiac catheterization for acute myocardial infarction, adjusted mortality rates and utilization of postlysis revascularization are similar in women and men. However, women may be at increased risk for reinfarction.

Clinical importance of thrombocytopenia occurring in the hospital phase after administration of thrombolytic therapy for acute myocardial infarction. The Thrombolysis and Angioplasty in Myocardial Infarction Study Group.

OBJECTIVES: The purpose of this study was to examine the incidence and clinical implications of thrombocytopenia that occurs in hospital after administration of thrombolytic therapy for acute myocardial infarction. BACKGROUND: The use of thrombolytic therapy in patients with acute myocardial infarction has improved mortaltiy rates, but hemorrhage remains a major complication. Because thrombocytopenia may be associated with hemorrhage after thrombolytic therapy, we examined the incidence and clinical implications of thrombocytopenia after administration of thrombolytic therapy for acute myocardial infarction. METHODS: The patient population comprised 1,001 patients enrolled in Phases 2, 3 and 5 of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trial and the urokinase trial. Patients received recombinant tissue-type plasminogen activator, urokinase or combination therapy in various dosing schemes. All patients received heparin, aspirin and a calcium-channel blocking agent. Thrombocytopenia occurring anytime after thrombolytic therapy was defined as a nadir platelet count either < 100,000/microliters or < 1/2 baseline. Blood loss was quantified by a bleeding index. Multiple logistic regression was used to evaluate the independent contribution of thrombocytopenia in a model predicting in-hospital mortality. RESULTS: Thrombocytopenia occurred in 16.4% of patients, with no difference among the thrombolytic regimens. Patients with thrombocytopenia had a lower median acute ejection fraction and a higher likelihood of three-vessel coronary artery disease than patients without thrombocytopenia. Patients with thrombocytopenia had more hemorrhage, a higher in-hospital mortality rate and a more complicated hospital course than patients without thrombocytopenia, even after consideration of other important variables, including age, acute ejection fraction, number of diseased vessels, bypass surgery and use of intraaortic balloon counterpulsation. CONCLUSIONS: Thrombocytopenia after thrombolytic therapy is a common event and is associated with excess hemorrhage and mortality. Platelet counts should be monitored daily after administration of thrombolytic therapy because the appearance of thrombocytopenia identifies a subset of patients at increased risk for hemorrhage and death.

Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) Study Group.

OBJECTIVES: This study sought to determine the frequency of thrombocytopenia and its relation with clinical outcomes in high risk patients undergoing percutaneous coronary revascularization who received either the platelet glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (ReoPro, c7E3 Fab) or conventional therapy. BACKGROUND: The development of thrombocytopenia on exposure to GPIIb/IIIa antagonists threatens the utility and economic viability of this drug class for patients with vascular disease. METHODS: We analyzed data from the Evaluation of c7E3 for the Prevention of Ischemic Complications trial (EPIC), a 2,099-patient, randomized trial of placebo, abciximab bolus or abciximab bolus plus a 12-h infusion during high-risk coronary revascularization. RESULTS: Thrombocytopenia (nadir platelet count <100 x 10(9)/ liter) developed in 81 patients (3.9%) during their hospital stay, with 19 (0.9%) developing severe (<50 x 10(9)/liter) thrombocytopenia. Both thrombocytopenia and severe thrombocytopenia were more frequent in the bolus-plus-infusion arm (5.2% and 1.6%, respectively) than in the bolus-only and placebo arms combined (p = 0.020 and p = 0.025, respectively). Acute profound thrombocytopenia developed in two patients in the bolus-plus-infusion arm. Patients with thrombocytopenia experienced more unfavorable clinical outcomes than those who did not develop thrombocytopenia, regardless of treatment assignment, but those with thrombocytopenia who received abciximab had fewer worse outcomes at 30 days. Multivariable logistic modeling revealed a lower baseline platelet count, older age and lighter weight to be important predictors of thrombocytopenia. In a logistic regression model, bolus-plus-infusion treatment was a significant predictor of thrombocytopenia (p = 0.016) and remained so after adjustment for procedures and baseline risk factors (p = 0.0077). CONCLUSIONS: Thrombocytopenia was associated with adverse clinical outcomes and excessive bleeding, but patients receiving abciximab fared better than those receiving placebo.

Determinants of the need for early acute intervention in patients treated conservatively after thrombolytic therapy for acute myocardial infarction. TAMI-5 Study Group.

This study sought to determine whether clinical variables can be used to identify patients at high risk of recurrent spontaneous myocardial ischemia or hemodynamic compromise during the 1st 4 days after intravenous thrombolysis for acute myocardial infarction. Of 288 patients randomly assigned to a conservative postthrombolysis strategy, 54 (19%) required urgent cardiac catheterization within 24 h; 75 (26%) underwent urgent cardiac catheterization within 4 days of admission. Of the clinical variables examined by multiple logistic regression analysis, only patient age and anterior wall myocardial infarction correlated with the need for urgent cardiac catheterization (p = 0.0016 and p = 0.017, respectively). Compared with recombinant tissue-type plasminogen activator or urokinase monotherapy, combination therapy with these agents was associated with a lower need for acute intervention during the 1st 24 h after admission, but the difference did not reach statistical significance (14% for combination therapy vs. 21% for each agent alone, p = 0.30). Of the 75 patients undergoing urgent coronary angiography, only 39% had an occluded infarct-related artery. Emergency coronary angioplasty was performed in 49% of the patients and coronary artery bypass graft surgery was performed urgently in 3%. Despite these interventions, the need for urgent cardiac catheterization was associated with an in-hospital mortality rate of 7% (vs. 3% in the group not requiring urgent angiography, p = 0.36); mean left ventricular ejection fraction was 50.5 +/- 11% (vs. 54.3 +/- 10.8%, p = 0.12) and regional infarct zone wall motion was -2.68 +/- 1.07 SD/chord (vs. -2.46 +/- 1.19 SD/chord; p = 0.44).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. IMPACT-II Investigators. Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II.

OBJECTIVES: We examined the relations of elevated creatine kinase (CK) and its myocardial band isoenzyme (CK-MB) to clinical outcomes after percutaneous coronary intervention (PCI) in patients enrolled in Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II (trial) (IMPACT-II), a trial of the platelet glycoprotein IIb/IIIa inhibitor eptifibatide. BACKGROUND: Elevation of cardiac enzymes often occurs after PCI, but its clinical implications are uncertain. METHODS: Patients undergoing elective, scheduled PCI for any indication were analyzed. Parallel analyses investigated CK (n=3,535) and CK-MB (n=2,341) levels after PCI (within 4 to 20 h). Clinical outcomes at 30 days and 6 months were stratified by postprocedure CK and CK-MB (multiple of the site's upper normal limit). RESULTS: Overall, 1,779 patients (76%) had no CK-MB elevation; CK-MB levels were elevated to 1 to 3 times the upper normal limit in 323 patients (13.8%), to 3 to 5 times normal in 84 (3.6%), to 5 to 10 times normal in 86 (3.7%), and to >10 times normal in 69 patients (2.9%). Elevated CK-MB was associated with an increased risk of death, reinfarction, or emergency revascularization at 30 days, and of death, reinfarction, or surgical revascularization at 6 months. Elevated total CK to above three times normal was less frequent, but its prognostic significance paralleled that seen for CK-MB. The degree of risk correlated with the rise in CK or CK-MB, even for patients with successful procedures not complicated by abrupt closure. CONCLUSIONS: Elevations in cardiac enzymes, including small increases (between one and three times normal) often not considered an infarction, are associated with an increased risk for short-term adverse clinical outcomes after successful or unsuccessful PCI.

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.

Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction.

PURPOSE: Little attention has been paid to the importance of clinical factors associated with bleeding complications caused by the use of thrombolytic agents. The goal of our study was to examine clinical and hematologic factors associated with an increased risk of bleeding in a prospectively observed population that received intravenous tissue plasminogen activator for acute myocardial infarction. PATIENTS AND METHODS: Bleeding complications were evaluated in 386 consecutive patients treated with 150 mg of tissue plasminogen activator over six to eight hours for acute myocardial infarction. All patients also underwent immediate cardiac catheterization. RESULTS: Quantitation of blood loss during the patients' hospital stay included a median drop in hematocrit of 11.4 points, a median nadir hematocrit of 31.2, a 14 percent rate of significant clinically evident bleeding, and a 31 percent rate of transfusion of two or more units of blood. All of these parameters were much more severe in patients treated with coronary artery bypass surgery. Access site hematoma was the most common source of bleeding (45 percent of patients), whereas 8 percent had gastrointestinal bleeding, two patients had retroperitoneal bleeding, and two patients had intracranial bleeding. The median nadir fibrinogen was 1.3 g/liter. Multiple linear regression models were used to investigate the relationship between clinical variables, including multiple hematologic measurements, and measures of the amount of blood loss. The use of coronary artery bypass grafting was the variable most closely associated with hemorrhage. Other invasive procedures (angioplasty and intra-aortic balloon pumping) were also associated with increased bleeding. Among the patient descriptors examined, lighter weight, older age, female sex, and history of hypertension were associated with greater blood loss. Of laboratory coagulation parameters, only nadir fibrinogen levels were significantly associated with more bleeding. CONCLUSION: Careful clinical evaluation may improve assessment of the risk/benefit ratio of thrombolytic therapy.

Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with tissue plasminogen activator for acute myocardial infarction.

Baseline plasminogen activator inhibitor (PAI) levels were examined for their influence on the responses to thrombolysis with recombinant tissue plasminogen activator (rt-PA) administered for acute myocardial infarction during the Thrombolysis and Myocardial Infarction (TAMI)-I study. Baseline PAI activity was 19 +/- 21 IU/ml (normal less than 5 IU/ml) and baseline PAI-1 antigen 54 +/- 53 ng/ml (normal 27 +/- 16 ng/ml), confirming previous findings of elevated PAI levels during acute myocardial infarction. Among clinical outcomes, lower PAI-1 antigen levels correlated weakly with greater patency at the 90 min angiogram. Thus, high baseline plasma PAI-1 levels may be detrimental to reperfusion with t-PA. There was no correlation with other major in-hospital clinical outcomes including reocclusion at the 7-10 day angiogram, survival to discharge, or bleeding. During the follow up period of 2.0 +/- 0.4 years, no relationship between baseline PAI levels and post-discharge reinfarction was observed.

Significance of a coronary artery with thrombolysis in myocardial infarction grade 2 flow "patency" (outcome in the thrombolysis and angioplasty in myocardial infarction trials). Thrombolysis and Angioplasty in Myocardial Infarction Study Group.

To determine whether pharmacologic reperfusion to Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow during acute myocardial infarction confers the same clinical benefit as restoration of TIMI 3 flow, in-hospital clinical and angiographic outcomes in 1,229 patients prospectively enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction trials were analyzed. Patients were treated with intravenous tissue plasminogen activator or urokinase, or both. Angiography of the infarct-related artery 90 minutes after initiation of thrombolytic therapy demonstrated TIMI grades 0, 1, 2, or 3 flow in 20%, 7%, 17%, and 55% of vessels, respectively. Rescue or adjunctive coronary angioplasty was performed in 80%, 27%, and 16% of patients with TIMI 0/1, 2, or 3 flow, respectively. Predischarge angiography was performed in 963 patients. A significant gradient of increasing mortality was seen in patients with lower TIMI flow (4.3%, 6.1%, and 10.1% with TIMI 3, 2, and 0/1 flow, respectively, p = 0.002). The incidence of congestive heart failure and recurrent ischemia was significantly higher in patients with TIMI 2 than with TIMI 3 perfusion (26% vs 19% for heart failure, p = 0.03; 23% vs 17% for recurrent ischemia, p = 0.05). Acute left ventricular ejection fraction and infarct zone regional wall motion were also significantly improved in patients with TIMI 3 than with TIMI 2 flow, with trends toward better improvement in global and regional function in the TIMI 3 group. These findings were not affected by the use of acute coronary angioplasty.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of eptifibatide on angiographic complications during percutaneous coronary intervention in the IMPACT--(Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) II Trial.

We sought to determine whether eptifibatide reduces elevation of creatine kinase (CK)-MB isoenzyme release during coronary intervention by preventing angiographic complications, by minimizing the sequelae of angiographic complications once they occur, or by other mechanisms. In the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis trial, patients underwent coronary intervention during treatment with placebo versus the glycoprotein IIb/IIIa receptor inhibitor eptifibatide. Eptifibatide decreased ischemic complications at 24 hours and 30 days. CK-MB elevations and in-laboratory angiographic complications (including major dissection, distal embolization, residual thrombus, abrupt closure, residual stenosis >50%, and side branch occlusion) were prospectively recorded. The incidence of any angiographic complication was lower in eptifibatide-treated patients (33%) than in placebo-treated patients (38%, p = 0.019). For patients with angiographic complications, there was a trend toward a reduced incidence of any elevation in CK-MB in the first 24 hours (29%, 135/0.75 eptifibatide dose; 33%, 135/0.5 eptifibatide dose; 37%, placebo). Among patients without angiographic complications, there was a similar trend toward fewer abnormal CK-MB levels in patients receiving eptifibatide (17% and 18% in eptifibatide arms vs 21% placebo). Thus, eptifibatide reduces angiographically evident complications during coronary intervention, but this effect accounts for only 1/3 of the reduced frequency of CK-MB elevations observed with eptifibatide. When angiographic complications occur, eptifibatide reduces rates of subsequent CK-MB elevation, accounting for another 1/3 of the reduction in CK-MB elevations. Finally, eptifibatide reduces the incidence of periprocedural CK-MB elevations in patients without angiographically evident complications, accounting for 1/3 of eptifibatide's overall effect in reducing of CK-MB elevations in patients undergoing percutanous coronary intervention.

Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (the EPIC trial). Evaluation of c7E3 Fab in the Prevention of Ischemic Complications trial.

The activated clotting time (ACT) has been used during percutaneous transluminal coronary angioplasty (PTCA) to monitor the extent of thrombin inhibition and anti-coagulation from heparin in an attempt to minimize untoward thrombotic events and hemorrhagic complications. With the introduction of potent platelet inhibitors, such as the chimeric monoclonal antibody c7E3, to interventional cardiology, the utility of measuring and regulating procedural ACT has not been examined. To investigate the possible influence of platelet IIb/IIIa antagonism on procedural ACT, we reviewed data from the Evaluation of c7E3 Fab in the Prevention of Ischemic Complications (EPIC) trial. In the EPIC trial, 2,099 patients undergoing PTCA with a high risk of abrupt vessel closure were randomized to receive placebo (n = 696) or the IIb/IIIa platelet receptor antagonist c7E3 Fab (n = 1,403). Despite receiving less procedural heparin, and fewer patients receiving very high heparin doses (> 14,000 U) than the placebo group, those receiving c7E3 had a higher mean (401 vs 367 seconds, p < 0.001) ACT when corrected for body weight. The ACT is increased approximately 35 seconds by the platelet IIb/IIIa receptor antagonist c7E3 Fab. This has important implications for dosing conjunctive heparin therapy and performing PTCA or directional coronary atherectomy in the setting of IIb/IIIa-directed therapy.

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.

Timing of and risk factors for myocardial ischemic events after percutaneous coronary intervention (IMPACT-II). Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

We studied both the time course and risk factors for adverse clinical events after percutaneous coronary intervention (PCI). Such information is critical to clinical decision-making, but scant quantitative data exist to describe the time course of these adverse outcomes. Patients enrolled in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial were analyzed. Patients undergoing elective, urgent, or emergency PCI (n = 4,010) were randomized to receive either placebo or 1 of 2 eptifibatide regimens during intervention. We evaluated the time to the primary end point of the trial, the 30-day composite of death, myocardial infarction, repeat nonelective PCI, nonelective bypass surgery, or stenting for abrupt closure. Adverse events occurred in 407 patients (10.1%). Because the risk of events declined substantially between 6 and 9 hours (66% occurred within 6 hours), events were classified as occurring before or after 6 hours. Independent predictors of "early" events included dissection, pre- and postprocedural coronary blood flow, side-branch occlusion, procedural thrombolytic use, previous bypass, presentation with unstable angina, absence of diabetes, and hyperlipidemia. The predictors of "late" events included lower weight, increased baseline heart rate, coronary dissection, and procedural thrombolytic use. The risk of ischemic events were greatest immediately after PCI and rapidly declined, so that by 9 hours the hazard function plot was flat; 66% of events occurred within 6 hours of PCI. Knowledge of the risk factors for early and late events help risk-stratify patients before and after intervention for myocardial ischemic events.

An analysis of the cause of early mortality after administration of thrombolytic therapy. The Thrombolysis Angioplasty in Myocardial Infarction Study Group.

BACKGROUND: The use of thrombolytic therapy in myocardial infarction has been associated with a considerable improvement in survival rate; however, almost 40% of the deaths during hospitalization occur during the first 24 h. Clinical and angiographic characteristics identified through careful comparison of those patients who die early with those who survive may serve as important targets for the development of new strategies for the management of myocardial infarction. METHODS: Medical records and autopsy reports of 810 patients enrolled into four sequential studies evaluating thrombolytic therapy and angioplasty in acute myocardial infarction were reviewed. All patients were enrolled into four similar protocols with administration of thrombolytic therapy (intravenous tissue plasminogen activator in 561 patients, urokinase in 102, and a combination of tissue plasminogen activator and urokinase in 147) and acute cardiac catheterization performed 90 min after starting therapy. RESULTS: The overall in-hospital mortality rate was 6.8% (55 out of 810), with 21 of these deaths (38%) occurring within the first day. The median (25th, 75th percentile) time to death was 3 (0, 12) days. Infarct location was more frequently anterior in patients who died within the first day. Patients who died 24 h after admission to hospital had the lowest patency rate (45%) compared with patients who died within 24 h (59%) and those who survived (71%, P = 0.003). The deaths within the first day were more likely to be a result of cardiogenic shock (48%), ventricular arrhythmias (14%), or cardiac rupture (9%), whereas late deaths were more likely to be a result of recurrent ischemia or reinfarction (32%) and non-cardiac causes (18%). Two patients had an intracranial hemorrhage within the first 24 h which caused immediate death in one and death on the third day of hospitalization in the other. CONCLUSION: Mortality within the first 24 h of thrombolytic therapy administration can be defined by inadequate myocardial reperfusion in patients with cardiac failure, possibly associated reperfusion injury leading to cardiac rupture, and an increased risk of intracranial hemorrhage. These factors may serve as targets for the development of new treatment strategies in acute myocardial infarction that may alter prognosis.

Transformation of measurements percentage of white coat color for Holsteins and estimation of heritability.

Percentage of white coat color was measured on registration certificates of 4293 Holstein heifers on eight dairy farms in Florida. Measurements of white percentage were by visual evaluation on one side of the upper body (head, neck, and trunk) only and obtained in increments of 5%. Mean, median, mode, standard deviation, and skewness of white percentage were 25.6, 15, 0, 26.9, and 1.03. Distribution of white percentages showed lack of normality. Original data were transformed using an extension of the Box-Cox transformation to approach normality and to provide maximum likelihood estimators of the transformed parameters. Heritability estimates for percentages of white coat color were computed using derivative-free REML with an animal model. Estimates of heritability were .715 from untransformed data and .779 for transformed. Standard errors of estimates were slightly lower (.032 vs. .035) following transformation. Additional study to find an improved transformation procedure still seems warranted.

Multivessel coronary artery disease: a key predictor of short-term prognosis after reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group.

Results of recent studies have suggested that routine cardiac catheterization may be unnecessary after reperfusion therapy for acute myocardial infarction. Therefore to better define the short-term prognostic value of early coronary angiography, and specifically the prognostic significance of multivessel coronary artery disease, the angiographic findings of 855 patients consecutively enrolled in five phases of the TAMI study were correlated with their in-hospital outcome. All patients received intravenous thrombolytic therapy (tissue plasminogen activator, urokinase, or both agents) and underwent cardiac catheterization within 90 minutes of the initiation of therapy. Multivessel disease, defined as the presence of greater than or equal to 75% luminal diameter stenosis in two or more major epicardial arteries, was documented in 236 patients. When compared with the group of patients without multivessel disease, this group had a higher prevalence of coronary risk factors and more frequently had a history of antecedent ischemic chest pain. Although the severity of the infarct zone dysfunction was similar in the two groups (-2.77 +/- 1.00 vs -2.50 +/- 1.09 SD/chord, p = NS), global left ventricular ejection fraction was lower in the group with multivessel disease (48.6 +/- 12.4% vs 51.8 +/- 10.6%, p less than 0.01). This was associated with a significant difference in the function of the noninfarct zone. Whereas this region was hyperkinetic in the group with minimal or single-vessel disease, it was hypocontractile or dyskinetic in those with multivessel disease (+0.66 +/- 1.53 vs -0.52 +/- 1.73 SD/chord, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrent ischemia without warning. Analysis of risk factors for in-hospital ischemic events following successful thrombolysis with intravenous tissue plasminogen activator.

Ischemic events after successful thrombolysis have been reported to occur in 18-32% of patients treated for acute myocardial infarction with thrombolytic therapy, and previous studies in which patients received streptokinase suggest that risk of early recurrent ischemia is closely related to the presence of a high-grade residual stenosis. If these events are predictable after intravenous recombinant tissue-plasminogen activator (rt-PA) thrombolytic therapy, then further intervention after its use could be targeted at selected patients. One-hundred ninety-two patients from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) I and TAMI III trials had successful rt-PA-mediated thrombolysis without immediate coronary angioplasty (PTCA). One-hundred seventy-four of these patients (92%) had prehospital discharge angiography. The mean age was 56 +/- 11 years; 81% were men; the infarct-related artery was the left anterior descending in 76 (39.8%), the left circumflex in 24 (12.6%), and the right coronary artery in 91 (47.6%). Thrombolysis with rt-PA resulted in a residual 73 +/- 13% diameter and 0.95 +/- 0.51 mm stenosis by quantitative coronary arteriography, and Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 in 59.2% and 3 in 40.8% of stenoses as assessed on angiograms obtained 90 minutes after the initiation of rt-PA therapy. Recurrent ischemic events (ischemia requiring emergency percutaneous transluminal coronary angioplasty or urgent bypass surgery, reocclusion of the infarct-related artery, or cardiac death) occurred in 41 patients (21.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. TAMI Study Group.

To determine the clinical consequences of reocclusion of an infarct-related artery after reperfusion therapy, we evaluated 810 patients with acute myocardial infarction. Patients were admitted into four sequential studies with similar entry criteria in which patency of the infarct-related artery was assessed by coronary arteriography 90 minutes after onset of thrombolytic therapy. Successful reperfusion was established acutely in 733 patients. Thrombolytic therapy included tissue-type plasminogen activator (t-PA) in 517, urokinase in 87, and a combination of t-PA and urokinase in 129 patients. All patients received aspirin, intravenous heparin and nitroglycerin, and diltiazem during the recovery phase. A repeat coronary arteriogram was performed in 88% of patients at a median of 7 days after the onset of symptoms. Reocclusion of the infarct-related artery occurred in 91 patients (12.4%), and 58% of these were symptomatic. Angiographic characteristics at 90 minutes after thrombolytic therapy that were associated with reocclusion compared with sustained coronary artery patency were right coronary infarct-related artery (65% versus 44%, respectively) and Thrombolysis in Myocardial Infarction (TIMI) flow 0 or 1 (21% versus 10%, respectively) before further intervention. Median (interquartile value) degree of stenosis in the infarct-related artery at 90 minutes was similar between groups: 99% for reoccluded (value, 90/100%) compared with 95% for patent (value, 80/99%). Patients with reocclusion had similar left ventricular ejection fractions compared with patients with sustained patency at follow-up. However, patients with reocclusion at follow-up had worse infarct-zone function at -2.7 (value, -3.2/-1.8) versus -2.4 (SD/chord) (value, -3.1/-1.3) (p = 0.016). The recovery of both global and infarct-zone function was impaired by reocclusion of the infarct-related artery compared with maintained patency; median delta ejection fraction was -2 compared with 1 (p = 0.006) and median delta infarct-zone wall motion was -0.10 compared with 0.34 SD/chord (p = 0.011), respectively. In addition, patients with reocclusion had more complicated hospital courses and higher in-hospital mortality rates (11.0% versus 4.5%, respectively; p = 0.01). We conclude that reocclusion of the infarct-related artery after successful reperfusion is associated with substantial morbidity and mortality rates. Reocclusion is also detrimental to the functional recovery of both global and infarct-zone regional left ventricular function. Thus, new strategies in the postinfarction period need to be developed to prevent reocclusion of the infarct-related artery.

Clinical risk factors for ischemic complications after percutaneous coronary interventions: results from the EPIC trial. The EPIC Investigators.

BACKGROUND: Most analyses of complications after percutaneous coronary intervention have been limited to angiographic predictors of abrupt closure. We sought to determine the relation between baseline clinical and angiographic characteristics and clinical ischemic events and whether treatment with the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 reduced ischemic events differentially in patients with distinct lesion morphologic characteristics. In the EPIC trial, a bolus and infusion of c7E3 decreased the 30-day incidence of death, myocardial infarction, and need for revascularization by 35% in 2099 high-risk patients. METHODS: We used logistic regression modeling to determine the relations between these patients' baseline clinical and angiographic characteristics and the composite primary end point. We also constructed multivariable models with interaction terms to assess treatment effect on prespecified, core laboratory-assessed, coronary morphologic characteristics. RESULTS: The most important predictors of a poor outcome were low weight (chi-square = 10.5, P =.001) and preprocedural percent stenosis (chi-square = 15.0, P <.001). History of hypertension, nonwhite race, and peripheral vascular disease were also associated with an increased risk, as were all measures of lesion complexity except calcification and presence of a side branch. The treatment benefit with abciximab was significantly greater with less complex than with more complex lesion morphologic characteristics. CONCLUSIONS: Future risk models should include these baseline characteristics to define the risk for ischemic complications in individual patients, and treatment with abciximab should not be predicated on lesion morphologic findings alone.