James J. Ferguson

Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.

Dilatation of infarcted segments (infarct expansion) may occur during recovery from myocardial infarction, but the fate of noninfarcted segments is uncertain. Accordingly, left ventricular geometric changes were assessed by left ventricular angiography and M mode echocardiography on admission and 2 weeks later in 30 patients with their first acute transmural myocardial infarction. All patients demonstrated chest pain, ST segment elevation with subsequent development of Q waves (15 anterior, 15 inferior), and elevation of cardiac enzymes. Sequential left ventricular angiographic and hemodynamic findings were available in these patients by virtue of their participation in a study of thrombolysis in acute myocardial infarction. By that study design, all patients treated successfully with thrombolytic therapy and demonstrating improvement of flow in an occluded coronary artery underwent repeat cardiac catheterization. At 2 weeks there was a significant decrease in left ventricular and pulmonary capillary wedge pressures (p less than .01), whereas both left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume indexes increased (p less than .01). The increase in LVEDV correlated directly with the percentage of the ventriculographic silhouette that was akinetic or dyskinetic at the initial catheterization (r = .71, p less than .001). To assess regional changes in both infarcted and noninfarcted segments, serial endocardial perimeter lengths of both the akinetic-dyskinetic segments (infarction zone) and of the remainder of the cardiac silhouette (noninfarction zone) were measured in all patients who demonstrated at least a 20% increase in their LVEDV at 2 weeks after myocardial infarction. Notably, there was a mean increase of 13% in the endocardial perimeter length of infarcted segments and a 19% increase in the endocardial perimeter length of noninfarcted segments. Serial M mode echocardiographic studies showed no significant change in the wall thickness of noninfarcted myocardial segments. Hemodynamic changes that occurred in this subgroup of patients included significant decreases in left ventricular end-diastolic and pulmonary capillary wedge pressures (p less than .05) and significant increases in angiographic cardiac index (p less than .01) and LVESV index (p less than .01). We conclude that in patients who manifest cardiac dilatation in the early convalescent period after myocardial infarction, there is remodeling of the entire left ventricle including infarct expansion of akinetic-dyskinetic segments and volume-overload hypertrophy of noninfarcted segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Meeting Highlights American College of Cardiology 45th Annual Scientific Session, Orlando, Florida, March 24 to 27, 1996

Dr Frans Van de Werf, from the University Hospital Gasthuisberg in Leuven, Belgium, Drs Robert Califf and Christopher Granger from Duke University, Durham, NC, and Dr Eric Topol, from the Cleveland (Ohio) Clinic, presented the results of the GUSTO IIb study, a large, international, multicenter trial of heparin versus hirudin in patients with acute MI and unstable angina. A total of 12 142 qualifying patients (onset of symptoms within 12 hours and ischemic ECG changes) were stratified into two groups on the basis of whether or not ST-segment elevation was present and randomized to receive heparin or hirudin. The primary end point of the study was the 30-day incidence of death and MI. Because of prior experience with a high level of bleeding complications in GUSTO IIa, the doses of study drug (both heparin and hirudin) used in GUSTO IIb were significantly reduced from GUSTO IIa. Patients treated with hirudin were noted to require fewer adjustments to maintain therapeutic levels (a mean of two adjustments versus four with heparin), and there were more hirudin patients who did not require any dose adjustments (28.5% versus 5.4% with heparin). In the ST-segment elevation group (n=4131), there was marked benefit of hirudin at 24 hours in the incidence of death and MI but no significant differences between the hirudin and heparin groups in terms of severe bleeding events (1.1% with hirudin, 1.5% with heparin), stroke (1.3% with hirudin, 0.8% with heparin), death at 30 days (5.9% versus 6.3%), and reinfarction at 30 days (5.0% versus 6.0%). In the overall population, there was significant benefit with hirudin in death or MI at 24 hours (1.3% with hirudin and 2.1% with heparin, a 37% relative decrease; P <.001). However, with time, the relative benefits of hirudin declined. By 48 hours, the incidence of death or MI …

The current practice of intra-aortic balloon counterpulsation: results from the Benchmark Registry ☆

OBJECTIVES This study presents clinical data from the first large registry of aortic counterpulsation, a computerized database that incorporates prospectively gathered data on indications for intra-aortic balloon counterpulsation (IABP) use, patient demographics, concomitant medication and in-hospital outcomes and complications. BACKGROUND The intra-aortic balloon pump (IABP) is widely used to provide circulatory support for patients experiencing hemodynamic instability due to myocardial infarction, cardiogenic shock, or in very high risk patients undergoing angioplasty or coronary artery bypass grafting. METHODS Between June 1996 and August 2000, 203 hospitals worldwide (90% U.S., 10% non-U.S.) collected 16,909 patient case records (68.8% men, 31.2% women; mean age 65.9 +/- 11.7 years). RESULTS The most frequent indications for use of IABP were as follows: to provide hemodynamic support during or after cardiac catheterization (20.6%), cardiogenic shock (18.8%), weaning from cardiopulmonary bypass (16.1%), preoperative use in high risk patients (13.0%) and refractory unstable angina (12.3%). Major IABP complications (major limb ischemia, severe bleeding, balloon leak, death directly due to IABP insertion or failure) occurred in 2.6% of cases; in-hospital mortality was 21.2% (11.6% with the balloon in place). Female gender, high age and peripheral vascular disease were independent predictors of a serious complication. CONCLUSIONS This registry provides a useful tool for monitoring the evolving practice of IABP. In the modern-day practice of IABP, complication rates are generally low, although in-hospital mortality remains high. There is an increased risk of major complications in women, older patients and patients with peripheral vascular disease.

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.

Bleeding Complications With the Chimeric Antibody to Platelet Glycoprotein IIb/IIIa Integrin in Patients Undergoing Percutaneous Coronary Intervention

BACKGROUND The potential for novel antiplatelet and antithrombin agents to contribute to periprocedural bleeding complications of percutaneous coronary revascularization is poorly defined. In the Evaluation of c7E3 Fab in Preventing Ischemic Complications of High-Risk Angioplasty (EPIC) trial, the periprocedural use of aspirin, heparin, and a chimeric antibody to the platelet glycoprotein IIb/IIIa integrin c7E3 Fab in 2099 patients significantly reduced postprocedural ischemic complications and 6-month clinical restenosis but was associated with increased procedural bleeding complications. We review these complications and describe clinical and procedural variables associated with increased bleeding complications in the EPIC trial. METHODS AND RESULTS Patients with high-risk clinical or lesion morphological characteristics were randomized to receive placebo bolus plus placebo infusion, c7E3 Fab bolus plus placebo infusion, or c7E3 Fab bolus plus c7E3 Fab infusion. Patients received periprocedural aspirin and intravenous heparin continued for a minimum of 12 hours after the procedure. Outcomes reflecting bleeding complications were measured: transfusions, decreased hemoglobin, and an index including both parameters. Major bleeding complications unrelated to bypass surgery occurred in 3.3%, 8.6%, and 10.6%, and blood product transfusions were used in 7.5%, 14.0%, and 16.8% of patients treated with placebo, bolus c7E3 Fab, and bolus plus infusion c7E3 Fab, respectively (both P < .001). Most major bleeding complications occurred at the femoral access site, regardless of treatment. Intracranial hemorrhage (0.3%) and death (0.09%) attributable to major bleeding complications were rare. Multivariable regression analyses identified several variables significantly and independently related to major bleeding complications or greater blood loss, including greater age, female sex, lower weight, c7E3 Fab therapy, and duration and complexity of the index procedure. Major bleeding complications and blood loss in patients receiving bolus plus infusion were not significantly greater than in those receiving bolus alone (P = .38 and P = .14, respectively). CONCLUSIONS Bleeding complications unrelated to bypass surgery were two to three times more frequent in patients receiving c7E3 Fab than in those receiving placebo, but most were transient and well tolerated. Risk-factor analysis and modification of concomitant antithrombotic and antiplatelet treatment strategies may aid in reducing bleeding complications and enhancing clinical benefit in patients receiving c7E3 Fab during percutaneous coronary revascularization.

Use of a direct antithrombin, hirulog, in place of heparin during coronary angioplasty.

BackgroundSince the inception of coronary angioplasty, heparin with or without aspirin has been routinely given intraprocedurally to avoid coronary thrombotic complications. Recently, the direct thrombin inhibitor hirulog has been demonstrated to inactivate clot-bound thrombin. The present study was a multicenter dose escalation of hirulog to determine its appropriate dose and feasibility as the sole anticoagulant during coronary angioplasty. Methods and ResultsAt 11 participating centers, 291 patients undergoing elective coronary angioplasty and pretreated with 325 mg aspirin daily were enrolled in sequential groups of intravenously administered hirulog instead of heparin as follows: group 1: bolus, 0.15 mg/kg; infusion, 0.6 mg · kg-1 hr1 (54 patients); group 2: bolus, 0.25 mg/kg; infusion, 1.0 mg· kg-1 hr-1 (53 patients); group 3: bolus, 0.35 mg/kg; infusion, 1.4 mg · kg-1 hr-1 (44 patients); group 4: bolus, 0.45 mg/kg; infusion, 1.8 mg · kg-1 hr-1 (74 patients); and group 5: bolus, 0.55 mg/kg; infusion, 2.2 mg· kg-1 hr-1 (54 patients). The hirulog infusion was maintained for 4 hours; the primary end point was abrupt vessel closure within 24 hours of the initiation of the procedure. Activated clotting times (ACT) and activated partial thromboplastin times (aPIT) were serially monitored. Abrupt vessel closure occurred in 18 patients (6.2%). By intention to treat, the abrupt closure event rate for groups 1-3 was 11.3% compared with 3.9% in groups 4 and 5 (p=0.052). There were no significant bleeding complications except for one patient in group 1, who received a two-unit transfusion. A dose-response curve of both ACTs and aPfTs was noted; no coronary thrombotic closures occurred in the small number of patients with ACT >300 seconds. ConclusionsThe present study documents for the first time that it is possible to perform coronary angioplasty with an anticoagulant other than heparin in aspirin-pretreated patients. Hirulog was associated with a rapid onset, dose-dependent anticoagulant effect, minimal bleeding complications, and at doses of 1.8-2.2 mg/kg, a rate of 3.9% for abrupt vessel closure.

Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries

BackgroundThis study was designed to test the hypothesis that endogenously produced nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries of mongrel dogs Methods and ResultsNG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide formation, was administered at 5 mg/kg to 15 dogs after the left anterior descending coronary artery was mechanically injured and narrowed by external constrictors and to nine dogs before endothelial injury of the femoral artery and after injury and moderate arterial constriction. Treatment with L-NMMA resulted in cyclic flow variations (as detected by external Doppler flow probes) in the left anterior descending artery of seven of 15 dogs and in the femoral artery of four of nine dogs after endothelial injury. L-Arginine, the precursor for nitric oxide synthesis, was administered at 60 mg/kg and abolished cyclic flow variations in each of the 11 dogs. D-Arginine did not change the L-NMMA-induced cyclic flow variations. Saline infusion did not induce or change cyclic flow variations in any of the animals. Acetylcholine (1, 10, and 100 μg/min; n =9) was administered in the femoral artery of nine additional dogs before and after endothelial injury in moderately stenosed femoral arteries. Acetylcholine did not induce cyclic flow variations in any animal; however, it did increase the severity of cyclic flow variations that developed in severely stenosed arteries. The diameter of the femoral artery was measured by intravascular ultrasound imaging. L-NMMA caused vasoconstriction of normal arteries, but no change was detected in endothelium-injured arteries. In contrast, L-arginine caused vasodilation of normal arteries, but, again, no change was noted in endothelium-injured arteries. Acetylcholine dilated normal femoral arteries but constricted arteries with endothelial injury. In both in vitro and ex vivo platelet studies, L-NMMA enhanced platelet aggregation, whereas L-arginine significantly reduced platelet aggregation. D-Arginine and acetylcholine showed no effect on platelet aggregation ConclusionsPromotion of nitric oxide production decreases platelet aggregation and may eliminate cyclic flow variations, whereas a reduction in nitric oxide formation enhances platelet aggregation and may induce cyclic flow variations. Acetylcholine causes vasoconstriction at the femoral arterial site of endothelial injury and may increase the severity of cyclic flow variations.

Contemporary utilization and outcomes of intra-aortic balloon counterpulsation in acute myocardial infarction ☆: The benchmark registry

OBJECTIVES We sought to examine contemporary utilization patterns and clinical outcomes in patients with acute myocardial infarction (AMI) requiring intra-aortic balloon pump (IABP) counterpulsation. BACKGROUND Despite increasing experience with and broadened indications for intra-aortic counterpulsation, the current indications, associated complications, and clinical outcomes of IABP use in AMI are unknown. METHODS Between June 1996 and August 2001, data were prospectively collected from 22,663 consecutive patients treated with aortic counterpulsation at 250 medical centers worldwide; 5,495 of these patients had AMI. RESULTS Placement of an IABP in AMI patients was most frequently indicated for cardiogenic shock (27.3%), hemodynamic support during catheterization and/or angioplasty (27.2%) or prior to high-risk surgery (11.2%), mechanical complications of AMI (11.7%), and refractory post-myocardial infarction unstable angina (10.0%). Balloon insertions were successful in 97.7% of patients. Diagnostic catheterization was performed in 96% of patients, and 83% underwent coronary revascularization before hospital discharge. The in-hospital mortality rate was 20.0% (38.7% in patients with shock) and varied markedly by indication and use of revascularization procedures. Major IABP complications occurred in only 2.7% of patients, despite median use for three days, and early IABP discontinuation was required in only 2.1% of patients. CONCLUSIONS With contemporary advances in device technology, insertion technique, and operator experience, IABP counterpulsation may be successfully employed for a wide variety of conditions in the AMI setting, providing significant hemodynamic support with rare major complications in a high-risk patient population.

Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention

OBJECTIVES The goal of this study was to test: 1) if platelet glycoprotein IIb/IIIa (GP IIb/IIIa) blockade with abciximab bolus plus 12-h infusion reduces mortality after percutaneous coronary intervention (PCI); 2) if prevention of early myocardial infarction (MI) after PCI is a mechanism for reducing mortality; and 3) for risk factors for mortality after PCI. BACKGROUND Studies of PCI suggest that MI after intervention is predictive of mortality. Abciximab, a platelet GP IIb/IIIa receptor inhibitor, has consistently reduced the incidence of MI among PCI patients in several trials. The presumed mechanism is prevention of platelet thrombus associated with vessel wall injury and downstream embolization into the microcirculation. METHODS In eight trials, 5,154 patients were randomized to a regimen comprising conventional therapy plus a bolus of abciximab within 1 h before PCI followed by a 12-h infusion; 4,136 controls were randomized to conventional therapy alone. Patient follow-up from six months to three years was available. Survival differences are examined using proportional hazards regression and survival curves. RESULTS A hazard ratio of 0.71 (95% confidence interval 0.57 to 0.89; p = 0.003) suggests a mortality benefit with abciximab. The absolute reduction in mortality was estimated to be 0.5% through 30 days, 0.7% through six months, 0.9% through one year and 1.8% through three years. Early MI explained 18% of the observed mortality benefit at one year. Multivariate regression suggests that patients with advanced cardiovascular disease may derive the greatest mortality benefit from abciximab. CONCLUSIONS The evidence from 9,290 randomized PCI patients shows a mortality benefit provided by abciximab bolus plus 12-h infusion.