Prediction of enzymatic infarct size in ST-segment elevation myocardial infarction.

OBJECTIVES: Predictors of adverse outcomes following myocardial infarction (MI) are well established; however, little is known about what predicts enzymatically estimated infarct size in patients with acute ST-elevation MI. The Complement And Reduction of INfarct size after Angioplasty or Lytics trials of pexelizumab used creatine kinase (CK)-MB area under the curve to determine infarct size in patients treated with primary percutaneous coronary intervention (PCI) or fibrinolysis. METHODS: Prediction of infarct size was carried out by measuring CK-MB area under the curve in patients with ST-segment elevation MI treated with reperfusion therapy from January 2000 to April 2002. Infarct size was calculated in 1622 patients (PCI=817; fibrinolysis=805). Logistic regression was used to examine the relationship between baseline demographics, total ST-segment elevation, index angiographic findings (PCI group), and binary outcome of CK-MB area under the curve greater than 3000 ng/ml. RESULTS: Large infarcts occurred in 63% (515) of the PCI group and 69% (554) of the fibrinolysis group. Independent predictors of large infarcts differed depending on mode of reperfusion. In PCI, male sex, no prior coronary revascularization and diabetes, decreased systolic blood pressure, sum of ST-segment elevation, total (angiographic) occlusion, and nonright coronary artery culprit artery were independent predictors of larger infarcts (C index=0.73). In fibrinolysis, younger age, decreased heart rate, white race, no history of arrhythmia, increased time to fibrinolytic therapy in patients treated up to 2 h after symptom onset, and sum of ST-segment elevation were independently associated with a larger infarct size (C index=0.68). CONCLUSION: Clinical and patient data can be used to predict larger infarcts on the basis of CK-MB quantification. These models may be helpful in designing future trials and in guiding the use of novel pharmacotherapies aimed at limiting infarct size in clinical practice.

Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials.

OBJECTIVE: The previous Pexelizumab for Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery I (PRIMO-CABG I) trial (n = 3099) indicated that C5 complement inhibition with pexelizumab might reduce myocardial infarction (MI) and postoperative mortality. PRIMO-CABG II was designed to investigate the safety and efficacy of terminal complement inhibition in reducing perioperative MI and mortality in patients undergoing CABG surgery who have 2 or more predefined preoperative risk factors. METHODS: PRIMO-CABG II, a randomized, double-blind, placebo-controlled trial, enrolled 4254 patients undergoing CABG with or without valve surgery at 249 hospitals in North America and Western Europe from June 2004 to July 2005. The patients were randomly assigned to receive intravenous pexelizumab or placebo. The primary composite endpoint was the incidence of death or MI within 30 days of randomization. RESULTS: The PRIMO-CABG II trial did not meet its prespecified primary endpoint of death or MI at 30 days, the secondary endpoints of death at 30 days, or the development of new or worsening congestive heart failure (relative risk 0.91, 0.82, and 1.01, respectively; P > .05). However, in a combined analysis of both pivotal trials, PRIMO-CABG I and II (n = 7353), death at 30 days was significantly reduced for the greatest risk subset (n = 2156, pexelizumab 5.7% vs placebo 8.1%, P = .024). Furthermore, this mortality reduction persisted throughout the 180-day follow-up period (pexelizumab 11.1% vs placebo 14.4%, P = .036). CONCLUSIONS: Pexelizumab was associated with a nonsignificant 6.7% reduction in the primary composite endpoint of death or MI at postoperative day 30 in CABG patients enrolled in the PRIMO-CABG II trial, despite the suggestion of a more favorable treatment effect in the previous PRIMO-CABG I trial. However, an exploratory analysis of the combined PRIMO I and II data set using an established predictive risk model showed a mortality benefit for high-risk surgical patients.

Evaluation of mobilized peripheral blood CD34(+) cells from patients with severe coronary artery disease as a source of endothelial progenitor cells.

BACKGROUND AIMS: The distinction between hematopoietic stem cells (HSC) and endothelial progenitor cells (EPC) is poorly defined. Co-expression of CD34 antigen with vascular endothelial growth factor (VEGF) receptor (VEGFR2) is currently used to define EPC ( 1 ). METHODS: We evaluated the phenotypic and genomic characteristics of peripheral blood-derived CD34(+) cells in 22 granulocyte-colony-stimulating factor (G-CSF)-mobilized patients with severe coronary artery disease and assessed the influence of cell selection and storage on CD34(+) cell characteristics. RESULTS: The median CD34(+) cell contents in the products before and after enrichment with the Isolex 300i Magnetic Cell Selection System were 0.2% and 82.5%, respectively. Cell-cycle analysis showed that 80% of CD34(+) cells were in G0 stage; 70% of the isolated CD34(+) cells co-expressed CD133, a marker for more immature progenitors. However, less than 5% of the isolated CD34(+) cells co-expressed the notch receptor Jagged-1 (CD339) and only 2% of the isolated CD34(+) population were positive for VEGFR2 (CD309). Molecular assessment of the isolated CD34(+) cells demonstrated extremely low expression of VEGFR2 and endothelial nitric oxide synthase (eNOS) and high expression of VEGF-A. Overnight storage at 4 degrees C did not significantly affect CD34(+) cell counts and viability. Storage in liquid nitrogen for 7 weeks did not affect the percentage of CD34(+) cells but was associated with a 26% drop in cell viability. CONCLUSIONS: We have demonstrated that the majority of isolated CD34(+) cells consist of immature and quiescent cells that lack prototypic markers of EPC. High VEGF-A gene expression might be one of the mechanisms for CD34(+) cell-induced angiogenesis.

Baseline Q-wave surpasses time from symptom onset as a prognostic marker in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention.

OBJECTIVES: We assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Time from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes. METHODS: We evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed. RESULTS: Fifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized < or =3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF. CONCLUSIONS: Baseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637).

Integrating ancillary studies in a large clinical trial: the design and rationale of the APEX library.

The APEX library was a coordinated and integrated set of ancillary analyses and substudies that were a part of the large APEX-AMI trial. The library included electrocardiogram, angiographic, blood biomarker, genetics, and MRI components. Operationally, the goals and administration of the APEX library were developed concurrently with the design of the parent trial. The goal recruitment in the library was met due to this approach. These data will provide important insights into the pathobiology of acute myocardial infarction and the relationships between inflammation, thrombosis, genetics, and classic clinical markers from angiograms, electrocardiograms, and patient demographics. In conclusion, the APEX library is an example of successful collaboration among academic trial leaders, site investigators, and pharmaceutical sponsors. The operational paradigm of this effort should be considered in future investigations so that important advances in clinical care of disease can be realized efficiently.

Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial.

CONTEXT: Reperfusion with percutaneous transluminal coronary intervention (PCI) is effective at improving outcomes in patients with acute ST-elevation myocardial infarction (STEMI). However, in patients without prompt reestablishment of brisk coronary flow and tissue perfusion, mortality remains high, providing an opportunity for novel treatments, including anti-inflammatory agents. OBJECTIVE: To evaluate the effectiveness of pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement, as an adjunct to PCI in improving 30-day mortality from STEMI. DESIGN, SETTING, AND PATIENTS: This trial was a prospective, multicenter, double-blind, placebo-controlled, phase 3 study of the intravenous administration of pexelizumab in conjunction with primary PCI in STEMI with prespecified high-risk electrocardiographic findings. The trial was intended to enroll 8500 patients, but in conjunction with the US Food and Drug Administration enrollment was modified to 5745 patients presenting from 296 hospitals in 17 countries from July 13, 2004, to May 11, 2006. INTERVENTIONS: Two thousand eight hundred eighty-five patients were randomly assigned to receive placebo and 2860 to receive pexelizumab given as a 2-mg/kg intravenous bolus prior to PCI followed by 0.05-mg/kg per hour infusion over the subsequent 24 hours. Patients were randomized within 6 hours of symptom onset. MAIN OUTCOME MEASURES: The primary end point was all-cause mortality through day 30. Secondary end points were death through day 90 and the composite of death, cardiogenic shock, or congestive heart failure through days 30 and 90. RESULTS: No difference in mortality through day 30 was observed between the pexelizumab and placebo treatment groups, with 116 patients (4.06%) and 113 patients (3.92%) who died in the respective groups (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.80-1.35; log-rank P = .78). The composite end points of death, shock, or heart failure were also similar with 257 patients (8.99%) receiving pexelizumab and 265 patients (9.19%) receiving placebo at 30 days (HR, 0.98; 95% CI, 0.83-1.16; P = .81) and 293 patients (10.24%) receiving pexelizumab and 293 patients (10.16%) receiving placebo at 90 days (HR, 1.01; 95% CI, 0.86-1.19; P = .91). CONCLUSION: In this large clinical trial of patients treated with primary PCI for STEMI, mortality was low and unaffected by administration of pexelizumab. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00091637.

Effect of pexelizumab on mortality in patients with acute myocardial infarction or undergoing coronary artery bypass surgery: a systematic overview.

BACKGROUND: Recent trials evaluating the C5 complement inhibitor, pexelizumab, have shown that modulation of inflammation during ischemia/reperfusion in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass graft (CABG) surgery may improve clinical outcomes. METHODS: We performed a systematic overview of individual patient data from all completed randomized controlled trials of pexelizumab to evaluate the effect on all-cause mortality at 30 and 180 days after treatment. We used a random effects model and included all 5916 patients randomized in 4 clinical trials. Patients received placebo, pexelizumab bolus only or pexelizumab bolus followed by a 24-hour infusion. RESULTS: A significant reduction in mortality at 30 days was observed in patients treated with bolus plus infusion (n = 2476) compared with placebo (n = 2492) (2.9% vs 4.2%; relative risk [RR], 0.70; 95% confidence interval [CI], 0.52-0.95; P = .02), with no interaction according to disease state of CABG or acute MI (P for interaction .33). A trend toward a reduction in mortality was observed in patients who received bolus plus infusion or bolus only (n = 3429) compared with placebo (n = 2476) (3.5% vs 4.2%; RR, 0.85; 95% CI, 0.66-1.0975; P = .215), but not in patients who received bolus only (n = 937) compared with placebo (n = 937) (5.2% vs 5.4%; RR, 0.96; 95% CI, 0.66-1.41; P = .918). The mortality benefit with bolus plus infusion compared with placebo persisted through 180 days (P = .05). CONCLUSIONS: Pexelizumab reduced 30-day mortality in this systematic evaluation. Bolus plus infusion dose is being studied in ongoing trials in acute MI and CABG populations.

Effect of pexelizumab in coronary artery bypass graft surgery with extended aortic cross-clamp time.

BACKGROUND: Prolonged cross-clamp time during cardiac surgery increases the risk of postoperative mortality and myocardial injury. This subanalysis from the pexelizumab for reduction of infarction and mortality in coronary artery bypass grafting surgery (PRIMO-CABG) trial, a phase III double-blind, placebo-controlled study of 3,099 patients undergoing on-pump coronary artery bypass graft surgery with or without valve surgery, assessed the impact of pexelizumab, an investigational C5 complement inhibitor, on postoperative outcomes after prolonged aortic cross-clamp time. METHODS: The composite endpoint of death or myocardial infarction through postoperative day 30 and death alone through days 30, 90, and 180 were examined in subpopulations of patients across different cross-clamp times. RESULTS: After prolonged cross-clamping (> or = 90 minutes), death, or myocardial infarction through day 30 and death through days 30, 90, and 180 were significantly increased in the intent-to-treat population and were even higher in patients with two or more prespecified risk factors, compared with all patients cross-clamped less than 90 minutes. Pexelizumab significantly reduced the incidence of death or myocardial infarction through day 30, and significantly reduced the incidence of mortality through day 180, in patients with two or more risk factors that required prolonged cross-clamp time. Pexelizumab also significantly reduced perioperative myocardial injury in all patients requiring prolonged cross-clamp time. CONCLUSIONS: In this retrospective, subgroup analysis, pexelizumab reduced postoperative morbidity and myocardial injury in patients with multiple risk factors who underwent prolonged cross-clamp time during coronary artery bypass surgery. The clinical benefit of pexelizumab may be related to the effect of complement inhibition in the presence of potential ischemic-reperfusion injury associated with prolonged aortic cross-clamp time.

Pexelizumab reduces death and myocardial infarction in higher risk cardiac surgical patients.

BACKGROUND: Morbidity and mortality after coronary artery bypass graft surgery are directly related to specific preoperative risk factors. We assessed the influence of preoperative risk factors on the effect of pexelizumab, a C5 complement inhibitor, to reduce postoperative morbidity and mortality in this post hoc analysis of the Pexelizumab for Reduction in Myocardial Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial, a phase III double-blind, placebo-controlled study of 3,099 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. METHODS: The composite endpoint of death or myocardial infarction or both through postoperative day 30 was examined in subpopulations of patients with pre-specified risk factors, which included diabetes mellitus, prior coronary artery bypass graft, urgent intervention, female sex, history of neurologic event, history of congestive heart failure, and two or more previous myocardial infarctions or a recent myocardial infarction. Stratified post hoc analyses were also performed on patients presenting with two or more and three or more of those risk factors. RESULTS: Pexelizumab significantly reduced the incidence of the composite endpoint of death or myocardial infarction through postoperative day 30 by 28% in patients with two or more risk factors (p = 0.004) and 44% in patients with three or more risk factors (p < 0.001). CONCLUSIONS: The C5 complement inhibitor, pexelizumab, reduced morbidity and mortality among high-risk patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial.

CONTEXT: Inflammation and ischemia-reperfusion injury during coronary artery bypass graft (CABG) surgery requiring cardiopulmonary bypass are associated with postoperative myocardial infarction (MI) and mortality. OBJECTIVE: To determine the efficacy and safety of pexelizumab, a C5 complement inhibitor, in reducing perioperative MI and mortality in CABG surgery. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial, including 3099 patients (> or = 18 years) undergoing CABG surgery with or without valve surgery at 205 hospitals in North America and Western Europe from January 2002 to February 2003. INTERVENTIONS: Patients were randomly assigned to receive intravenous pexelizumab (2.0 mg/kg bolus plus 0.05 mg/kg per hour for 24 hours; n = 1553) or placebo (n = 1546) 10 minutes before undergoing the procedure. MAIN OUTCOME MEASURES: The primary composite end point was the incidence of death or MI within 30 days of randomization in those undergoing CABG surgery only (n = 2746). Secondary analyses included the intent-to-treat analyses of death or MI composite at days 4 and 30 in all 3099 study patients. RESULTS: After 30 days, 134 (9.8%) of 1373 of patients receiving pexelizumab vs 161 (11.8%) of 1359 of patients receiving placebo (relative risk, 0.82; 95% confidence interval, 0.66-1.02; P =.07) died or experienced MI in the CABG surgery only population. In the intent-to-treat analyses, 178 (11.5%) of 1547 patients receiving pexelizumab vs 215 (14.0%) of 1535 receiving placebo died or experienced MI (relative risk, 0.82; 95% confidence interval, 0.68-0.99; P =.03). The trial was not powered to detect a reduction in mortality alone. CONCLUSIONS: Compared with placebo, pexelizumab was not associated with a significant reduction in the risk of the composite end point of death or MI in 2746 patients who had undergone CABG surgery only but was associated with a statistically significant risk reduction 30 days after the procedure among all 3099 patients undergoing CABG with or without valve surgery.