James E. Tcheng

Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty

BACKGROUND Thrombosis has been implicated as central to the clinical complications of coronary angioplasty (PTCA). Chimeric monoclonal 7E3 Fab (c7E3 Fab) is the first of a new class of antiplatelet drugs directed at the platelet glycoprotein IIb/IIIa integrin. This study was performed to determine the pharmacodynamics of c7E3 Fab administration during PTCA and to gain an initial clinical experience with this novel agent. METHODS AND RESULTS The study was a multicenter, open-label, dose-escalation study conducted in two stages. Enrollment included 56 patients scheduled for elective PTCA who were estimated to be at moderate to high risk of sustaining ischemic complications. All patients were given aspirin and heparin. The study drug was given at least 10 minutes before PTCA. In stage 1, increasing bolus doses of c7E3 Fab were given to 15 patients; a bolus dose of 0.25 mg/kg was found to result in blockade of > 80% of the receptors and reduce platelet aggregation to < 20% compared with baseline, establishing this dose as that necessary to sufficiently suppress platelet activity. In stage 2, additional c7E3 Fab was administered by continuous infusion to 32 patients for progressively longer periods of time (up to 24 hours) to confirm that platelet inhibition could be maintained with prolonged drug infusion. Also, 9 patients otherwise meeting entry criteria were given placebo. There were no thrombotic events among patients receiving c7E3 Fab. Overall procedural and clinical success and complication rates as well as rates of bleeding were statistically similar among groups. However, minor bleeding was more frequent with administration of the active drug. CONCLUSIONS The novel antiplatelet agent c7E3 Fab can be administered during PTCA in combination with aspirin and heparin. Suppression of platelet activity is dose dependent and can be maintained for up to 24 hours. Further evaluation will be required to determine the extent of improvement in ischemic complication and restenosis rates and to provide additional insight into the safety profile of this potent monoclonal platelet antibody.

Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic Heart Disease

BACKGROUND Several platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in clinical trials. We conducted a systematic overview (meta-analysis) to assess the effect of these compounds on death, myocardial infarction (MI), and revascularization. METHODS AND RESULTS ORs were calculated for 16 randomized, controlled trials of GP IIb/IIIa inhibitors. An empirical Bayesian random-effects model combined the outcomes of 32 135 patients. There was a significant mortality reduction by GP IIb/IIIa inhibitors at 48 to 96 hours, with an OR of 0.70 (95% CI, 0. 51 to 0.96; P<0.03), equivalent to a reduction of 1 death per 1000 patients treated. Mortality benefits at 30 days (OR, 0.87; 95% CI, 0. 74 to 1.02; P=0.08) and 6 months (OR, 0.97; 95% CI, 0.86 to 1.10; P=0.67) were not statistically significant. For the combined end point of death or MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at each time point. The 30-day OR was 0.76 (95% CI, 0.66 to 0.87), or 20 fewer events per 1000 patients treated. For the composite end point of death, MI, or revascularization, there was also a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors. At 30 days, the OR was 0.77 (95% CI, 0.68 to 0.86), or 30 fewer events per 1000 patients treated. The risk differences for death, death or MI, and composite outcomes were similar at 6 months, indicating a sustained absolute improvement. Similar benefit was seen when trials were subgrouped by therapeutic indication (percutaneous intervention versus acute coronary syndromes). CONCLUSIONS Application of this new therapeutic class to clinical practice promises substantial benefit for both indications.

Impact of Renal Insufficiency in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction

Background—The prognostic importance of renal insufficiency (RI) in patients undergoing primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) has not been well characterized. Methods and Results—PCI was performed in 2082 AMI patients without shock presenting within 12 hours of symptom onset in a prospective, multicenter randomized trial. RI was defined as a calculated (Cockroft-Gault) creatinine clearance (CrCl) ≤60 mL/min. RI at baseline was present in 18% of patients. Compared with patients without RI, patients with RI were older and were more likely to be female; to have hypertension, peripheral vascular disease, or cerebrovascular disease; and to present in heart failure. Mortality was markedly increased in patients with versus without baseline RI both at 30 days (7.5% versus 0.8%, P <0.0001) and at 1 year (12.7% versus 2.4%, P <0.0001). Mortality rates increased incrementally for every 10-mL/min decrease in baseline CrCl. By multivariate analysis, reduced baseline CrCl was a powerful independent predictor of 30-day mortality (hazard ratio, 5.77; P <0.0001) and remained associated with reduced survival at 1 year (hazard ratio, 1.98; P =0.08). Hemorrhagic complications and transfusion requirements were also increased more than 2-fold in patients with RI, as were severe restenosis (diameter stenosis ≥70%; 20.6% versus 11.8%, P =0.024) and infarct artery reocclusion (14.7% versus 7.3%, P =0.02). Conclusions—Baseline RI in patients with AMI undergoing primary PCI is associated with a markedly increased risk of mortality, as well as bleeding and restenosis. Novel approaches are needed to improve the otherwise poor prognosis of patients with RI and AMI.

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study☆

Background—The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. Methods and Results—Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACEs: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve ≥95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P =0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those ≥70% inhibited (P =0.009). By multivariate analysis, platelet function inhibition ≥95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P =0.04). Conclusions—Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

Restenosis after coronary angioplasty: An overview☆

Despite substantial basic and clinical efforts to address the problem of restenosis after percutaneous coronary intervention, effective preventive therapies have not yet been developed. Nevertheless, the accumulated information has provided much insight into the process of restenosis in addition to allowing standards to be developed for adequate clinical trials. The pathophysiology of restenosis increasingly appears to be distinct from that of primary atherosclerosis. Restenosis involves elastic recoil, incorporation of thrombus into the lesion and fibrocellular proliferation in varying degrees in different patients. Lack of an animal model that satisfactorily mimics restenosis is a major impediment to further understanding of the process. Clinical studies are hampered by difficulties in finding a single unifying definition of restenosis and by variable methods of reporting follow-up. Reporting of clinical outcomes of all patients in angiographic substudies would allow a more satisfactory interpretation of the results of clinical trials. Current noninvasive test results are not accurate enough to substitute for angiographic and clinical outcome data in intervention trials. In the majority of observational studies, only diabetes and unstable angina have emerged as consistently associated with restenosis; whereas most of the standard risk factors for atherosclerosis have a less consistent relation. Disappointingly, the new atherectomy and laser technologies have not affected restenosis rates. The one possible exception is coronary stenting, as a result of the larger luminal diameter achieved by the placement of the stent. In conclusion, although substantial continued effort is necessary to explore the basic aspects of cellular proliferation and mechanical alteration of atherosclerotic vessels, attention to the principles of clinical trials and observation are required to detect the impact of risk factors and interventions on the multifactorial problem of restenosis. Adequate sample sizes, collection of clinical and angiographic outcomes and factorial study designs hold promise for unraveling this important limitation of percutaneous intervention.

Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Platelet Integrin Glycoprotein IIb/IIIa Blocker Integrelin in Elective Coronary Intervention

Background Platelet aggregation and thrombosis have been implicated in the pathogenesis of coronary angioplasty complications. Integrelin, a synthetic cyclic heptapeptide with high affinity and marked specificity for platelet integrin glycoprotein IIb/IIIa, effectively blocks ADP-induced platelet aggregation. Methods and Results In 150 patients undergoing elective percutaneous coronary intervention, random assignment was made to one of three treatment regimens: placebo; a 90-μg/kg bolus of Integrelin before angioplasty followed by a 1.0-μg · kg−1 · min−1 infusion of Integrelin for 4 hours; or a 90-μg/kg bolus followed by a 1.0-μg · kg−1 · min−1 infusion of Integrelin for 12 hours. Patients were followed to 30 days for the composite occurrence of myocardial infarction, stent implantation, repeat urgent or emergency percutaneous intervention or coronary bypass surgery, or death. Pharmacodynamic data were obtained in a subset of 31 patients. Administration of a 90-μg/kg bolus of Integrelin achieved an 86% in...

2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards)

This document was approved by the American Heart Association Science A College of Cardiology Board of Trustees on November 12, 2014. The American College of Cardiology requests that this document be cited a Fonarow GC, Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW elements and definitions for cardiovascular endpoint events in clinical trials: Task Force on Clinical Data Standards (Writing Committee to Develop Cardi This article has been copublished in Circulation. Copies: This document is available on the World Wide Web sites of the Association (my.americanheart.org). For copies of this document, please con reprints@elsevier.com. Permissions: Multiple copies, modification, alteration, enhancement, and permission of the American College of Cardiology. Requests may be compl author-agreement/obtaining-permission). Marian C. Limacher, MD, FACC, FAHA Kenneth W. Mahaffey, MD, FACC Roxana Mehran, MD, FACC, FAHA Steven E. Nissen, MD, MACC, FAHA Eric E. Smith, MD, MPH, FAHA Shari L. Targum, MD, FACC*

Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial

Background—Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. Methods and Results—In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P =0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P =0.061 for intent-to-treat population). The primary reason for not completing treatment was ≥1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P <0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76±0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78±0.76 to 80 mm, P =0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm3, respectively;P =0.16 to 0.72). Conclusions—Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.

Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. EPIC Investigator Group. Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication.

CONTEXT Abciximab, a monoclonal antibody fragment against the platelet receptor alphaIIb beta3 integrin, prevents platelet aggregation. A randomized, placebo-controlled study showed that abciximab improves outcomes for patients undergoing percutaneous coronary angioplasty at 30 days and at 6 months. OBJECTIVE To determine whether abciximab improves outcomes 3 years after coronary angioplasty. DESIGN Double-blind, placebo-controlled, randomized trial. SETTING A total of 56 academic and community hospitals in the United States. PATIENTS A total of 2099 high-risk patients undergoing coronary angioplasty were randomized. Sufficient time elapsed for 2.5 years of follow-up among 2001 patients and for 3 years of follow-up among 1599 patients. INTERVENTIONS Abciximab bolus of 0.25 mg/kg followed by infusion at 10 microg/min for 12 hours; abciximab bolus of 0.25 mg/kg followed by placebo infusion; or placebo bolus followed by placebo infusion. MAIN OUTCOMES MEASURES The primary outcome was the composite of death, myocardial infarction, or coronary revascularization. Secondary outcomes were death, myocardial infarction, or coronary revascularization individually. Subgroups having refractory unstable angina or evolving myocardial infarction and having different elevations of creatine kinase during initial angioplasty were analyzed. RESULTS At 3 years, composite end points occurred in 41.1% of those receiving abciximab bolus plus infusion; 47.4% of those receiving abciximab bolus only; and 47.2% of those receiving placebo only (for abciximab bolus plus infusion vs placebo, P=.009). Death occurred in 6.8%, 8.0%, and 8.6%, respectively (for abciximab bolus plus infusion vs placebo, P=.20); myocardial infarction in 10.7%, 12.2%, and 13.6%, respectively (for abciximab bolus plus infusion vs placebo, P=.08); and revascularization in 34.8%, 38.6%, and 40.1%, respectively (for abciximab bolus plus infusion vs placebo, P=.02). Among those with refractory unstable angina or evolving myocardial infarction, death occurred in 5.1%, 9.2%, and 12.7%, respectively (for abciximab bolus plus infusion vs placebo, P=.01). Death rates increased as periprocedural creatine kinase levels increased. CONCLUSIONS Abciximab bolus with infusion given at the time of coronary angioplasty improves outcomes as long as 3 years after the procedure.

Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention

Abstract 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.