N. S. Kleiman

Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors

BACKGROUND Inhibition of the platelet glycoprotein IIb/IIIa receptor with the monoclonal-antibody fragment abciximab reduces the acute ischemic complications associated with percutaneous coronary revascularization, whereas coronary-stent implantation reduces restenosis. We conducted a trial to determine the efficacy of abciximab and stent implantation in improving long-term outcome. METHODS A total of 2399 patients were randomly assigned to stent implantation and placebo, stent implantation and abciximab, or balloon angioplasty and abciximab. The patients were followed for six months. RESULTS At six months, the incidence of the composite end point of death or myocardial infarction was 11.4 percent in the group that received a stent and placebo, as compared with 5.6 percent in the group that received a stent and abciximab (hazard ratio, 0.47; 95 percent confidence interval, 0.33 to 0.68; P<0.001) and 7.8 percent in the group assigned to balloon angioplasty and abciximab (hazard ratio, 0.67; 95 percent confidence interval, 0.49 to 0.92; P=0.01). The hazard ratio for stenting plus abciximab as compared with angioplasty plus abciximab was 0.70 (95 percent confidence interval, 0.48 to 1.04; P=0.07). The rate of repeated revascularization of the target vessel was 10.6 percent in the stent-plus-placebo group, as compared with 8.7 percent in the stent-plus-abciximab group (hazard ratio, 0.82; 95 percent confidence interval, 0.59 to 1.13; P=0.22) and 15.4 percent in the angioplasty-plus-abciximab group (hazard ratio, 1.49; 95 percent confidence interval, 1.13 to 1.97; P=0.005). The hazard ratio for stenting plus abciximab as compared with angioplasty plus abciximab was 0.55 (95 percent confidence interval, 0.41 to 0.74; P<0.001). Among patients with diabetes, the combination of abciximab and stenting was associated with a lower rate of repeated target-vessel revascularization (8.1 percent) than was stenting and placebo (16.6 percent, P=0.02) or angioplasty and abciximab (18.4 percent, P=0.008). CONCLUSIONS For coronary revascularization, abciximab and stent implantation confer complementary long-term clinical benefits.

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.

Mortality within 24 hours of thrombolysis for myocardial infarction. The importance of early reperfusion. The GUSTO Investigators, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

BackgroundA paradoxical increased risk of death has been reported during the first 24 hours after thrombolysis for myocardial infarction. The mechanism of this phenomenon is not known, nor is its relation to the success or failure of reperfusion. The present study was a prospectively designed analysis of deaths occurring within the first 24 hours in the GUSTO trial. Methods and ResultsThere were 41021 patients enrolled in GUSTO, a randomized comparison of streptokinase with intravenous or subcutaneous heparin, accelerated tissue-type plasminogen activator (TPA), and combination of streptokinase and TPA. An angiographic mechanistic substudy examined reperfusion (using the TIMI flow grading criteria) 90 minutes after the assigned thrombolytic regimen was begun in 1567 patients. There were 1125 deaths (2.8%) within 24 hours (“early deaths”) and 1726 additional deaths (4.2%) after 24 hours but within 30 days (“later deaths”). At the time of presentation, the most potent predictors of early death were hypotension and sinus tachycardia. In a multiple logistic regression model, lower systolic blood pressure, shorter height, higher heart rate, and the absence of prior smoking distinguished early death from later death. Reinfarction occurred in 26 patients (2.4%), shock in 572 patients (52%), atrioventricular block in 308 patients (28%), and tamponade in 106 patients (10%) dying early compared with 262 (15%), 788 (46%), 396 (23%), and 74 (4%) respective patients dying later. There were no differences in early mortality among the thrombolytic regimens for the first 6 hours after randomization. By 24 hours, however, mortality was 2.89% for streptokinase recipients, 2.84% for combination therapy recipients, and 2.36% for accelerated TPA recipients (P = .005). There was little difference among patients with differing flow grades in the infarct artery during the first 4 hours, although mortality was among patients with grade 2 flow was initially higher. After the fourth hour, there were very few additional deaths during the first day in patients with grade 3 flow. At 24 hours, mortality 2.35% for patients with flow grade 0 or 1, 2.92% for patients with flow grade 2, and 0.89% for patients with flow grade 3. ConclusionsEven with aggressive management regimens, mortality within the first 24 hours accounted for a large proportion of postthrombolytic deaths. Patients dying early were more likely to present with pump failure than were those dying later and were more likely to diet of events related to left ventricular dysfunction, although cardiac tamponade also accounted for a significant minority of these deaths. Thus, the severity of the clinical presentation rather than the underlying risk factors predicts early mortality. Based on the angiographic substudy data, it appears that rather than hastening early mortality, successful restoration of complete antegrade flow in the infarct-related artery protects against early death.

Impact of preprocedural white blood cell count on long term mortality after percutaneous coronary intervention: insights from the EPIC, EPILOG, and EPISTENT trials

Background: Raised inflammatory markers are associated with worse outcome after percutaneous coronary interventions (PCI). An increase in the white blood cell (WBC) count is a non-specific response to inflammation. We hypothesised that a raised baseline WBC count would be a predictor of mortality in patients undergoing PCI. Methods: The association between preprocedural WBC count and long term mortality was studied in 7179 patients enrolled in the EPIC, EPILOG, and EPISTENT trials. The end points were the incidence of myocardial infarction at one year, and one and three year mortality. Results: There were 188 deaths and 582 myocardial infarctions at one year. While WBC count was a strong predictor of death at one year, with every increase of 1 k/μl (1×106/l) being associated with a hazard ratio (HR) of 1.109 (95% confidence interval (CI) 1.072 to 1.147, p < 0.001), there was no association with myocardial infarction at one year (HR 1.020, 95% CI 0.990 to 1.052, p = 0.195). There were a total of 406 deaths at three years with a strong association between WBC count and three year mortality (HR for every 1 k/μl increase 1.089, 95% CI 1.058 to 1.121, p < 0.001). WBC count remained a significant predictor of mortality after multivariable adjustment (HR for every 1 k/μl increase 1.100, 95% CI 1.069 to 1.131, p < 0.001). The association was significant across multiple subgroups, including diabetes, female sex, clinical presentation, and cigarette smoking. Conclusion: A raised pre-procedural WBC count in patients undergoing PCI is associated with an increased risk of long term death. These results suggest a key role for inflammation in coronary artery disease.

Mechanical Complications After Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction (from APEX-AMI)

A decrease in mechanical complications after ST-elevation myocardial infarction may have contributed to improved survival rates associated with reperfusion by primary percutaneous coronary intervention (PCI). Mechanical complications occurred in 52 of 5,745 patients (0.91%) in the largest reported randomized trial in which primary PCI was the reperfusion strategy. The frequencies were 0.52% (30) for cardiac free-wall rupture (tamponade), 0.17% (10) for ventricular septal rupture, and 0.26% (15) for papillary muscle rupture (3 patients had 2 complications). Ninety-day survival rates were 37% (11) for cardiac free-wall rupture, 20% (2) for ventricular septal rupture, and 73.3% (11) for papillary muscle rupture. These mechanical complications occurred at a median of 23.5 hours (interquartile range 5.0 to 76.8) after symptom onset and were associated with 44% (23 of 52) survival through 90 days, which accounted for 11% of the 90-day mortality. Factors associated with mechanical complications were older age, female gender, Q waves, presence of radiologic pulmonary edema, and increased prerandomization troponin levels. In conclusion, rates of mechanical complications are lower with primary PCI than those previously reported after fibrinolytic therapy.

Comparison of outcome of patients with unstable angina and non-Q-wave acute myocardial infarction with and without prior coronary artery bypass grafting (Thrombolysis in Myocardial Ischemia III Registry)

The aim of this study was to characterize patients with and without prior coronary artery bypass grafting (CABG) among a prospectively identified cohort of patients presenting with unstable angina or non-Q-wave myocardial infarction. Patients in the Thrombolysis in Myocardial Infarction phase III Registry Prospective Study presented within 96 hours of an episode of unstable angina or non-Q-wave acute myocardial infarction. Of 2,048 patients, 336 (16.4%) had prior CABG. Compared with those without prior CABG, patients were the same age, but were more likely to be men, white, diabetic, have a history of angina or myocardial infarction, to have received anti-ischemic medications in the prior week, and to receive intravenous heparin or nitroglycerin, or both, during hospitalization. They were equally likely to undergo coronary angioplasty or CABG. Death or nonfatal myocardial infarction occurred by day 10 in 4.5% of patients with prior CABG and 2.8% of patients without prior CABG (p = 0.11); and by day 42 in 7.7% and 5.1%, respectively (p = 0.03). The composite of death, myocardial infarction, or recurrent ischemia at 1 year was more common among patients with prior CABG (39.3% vs 30.2%, p = 0.002). By multiple logistic regression, prior CABG was not independently associated with the occurrence of death or myocardial infarction, or the composite of death, myocardial infarction, or recurrent ischemia either at 6 weeks or at 1 year. The likelihood of recurrent ischemic events is greater among patients with than without prior CABG, but is not likely explained by differences in baseline or treatment characteristics which reflect the degree of underlying cardiac disease.

Redefining medical treatment in the management of unstable angina

In 1994, the Agency for Health Care Policy and Research sponsored the development of guidelines for diagnosing and managing patients with unstable angina. Since their publication, several important developments have occurred. The prognostic value of biochemical assays for cardiac-specific troponins T and I have been shown in many studies. The possible role for C-reactive protein in determining prognosis deserves further investigation. Substantial clinical benefits have been obtained with intravenous inhibitors of the platelet glycoprotein (GP) IIb-IIIa receptor (abciximab, eptifibatide, tirofiban) and with one of the low-molecular-weight heparins (enoxaparin). The therapeutic potential of other low-molecular-weight heparins, direct thrombin inhibitors, and oral GP IIb-IIIa inhibitors remains to be clarified. On the basis of this evidence, consideration should be given to measuring serum levels of a cardiac troponin (either T or I) and using intravenous GP IIb-IIIa inhibitors and low-molecular-weight heparin in the standard management of patients with unstable angina.

First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS Trial.

Summary.  Background: Unfractionated heparin is widely used in patients with non‐ST‐elevation acute coronary syndromes but has important limitations. Anticoagulants with predictable kinetics and anticoagulant effects, better efficacy, and greater safety are needed. Objective: To investigate the efficacy and safety of a direct, selective factor Xa inhibitor, DX‐9065a (Daiichi Pharmaceuticals LTD, Inc.) compared with heparin, in patients with non‐ST‐elevation acute coronary syndromes. Patients and methods: Patients (n = 402) from the USA, Canada, and Japan were randomized to blinded, weight‐adjusted heparin, low‐dose DX‐9065a, or high‐dose DX‐9065a. Results The primary efficacy endpoint of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST‐segment monitoring occurred in 33.6%, 34.3%, and 31.3% of patients assigned to heparin, low‐dose DX‐9065a, and high‐dose DX‐9065a (P = 0.91 for heparin vs. combined DX‐9065a). The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P = 0.125 for heparin vs. high‐dose DX‐9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients. Higher concentrations of DX‐9065a were associated with a lower likelihood of ischemic events (P = 0.03) and a non‐significant tendency toward a higher likelihood of major bleeding (P = 0.32). Conclusions: In this small phase II trial, there was a non‐significant tendency toward a reduction in ischemic events and bleeding with DX‐9065a compared with heparin in patients with acute coronary syndromes. The absence of an effect on ST‐monitor ischemia warrants further investigation. These data provide the rationale for adequately powered studies of DX‐9065a in acute coronary syndromes or percutaneous intervention.

The declining prevalence of ST elevation myocardial infarction in patients presenting with acute coronary syndromes

The management of patients with acute coronary syndromes may be about to undergo a dramatic change

A comparison of ionic versus nonionic contrast medium during primary percutaneous transluminal coronary angioplasty for acute myocardial infarction (GUSTO IIb)

The clinical impact of contrast medium selection during primary percutaneous transluminal coronary angioplasty for acute myocardial infarction (AMI) has not been studied. We compared the clinical outcomes of patients who received ionic versus nonionic low osmolar contrast medium in the setting of primary percutaneous transluminal coronary angioplasty for AMI in the second Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) trial. Univariable and multivariable analyses were performed to assess the relation between contrast medium selection and clinical outcome (death, reinfarction, or refractory ischemia) at 30 days. Although baseline clinical and angiographic characteristics were generally similar between the 2 groups, patients who received ionic, low osmolar contrast were less likely to have been enrolled at a US site (23% vs 43%, p = 0.001) and less likely to have occlusion of the left anterior descending coronary artery (34% vs 47%, p = 0.03) or a history of prior AMI (8% vs 16%, p = 0.02). The triple composite end point of death, reinfarction, or refractory ischemia occurred less frequently in the ionic group, both in the hospital (4.4% vs 11%, p = 0.018) and at 30 days (5.5% vs 11%, p = 0.044). Although the trend favoring ionic contrast persisted, the differences were no longer statistically significant after adjustment for imbalances in baseline characteristics using a risk model developed from the study sample (n = 454, adjusted odds ratio for ionic contrast 0.48 [0.22 to 1.02], p = 0.055), and using a model developed from the entire GUSTO IIb study cohort (n = 12,142, adjusted odds ratio for ionic contrast 0.50 [0.23 to 1.06], p = 0.072). The results of this observational study warrant further elucidation by a randomized study design in this setting.The clinical impact of contrast medium selection during primary percutaneous transluminal coronary angioplasty for acute myocardial infarction (AMI) has not been studied. We compared the clinical outcomes of patients who received ionic versus nonionic low osmolar contrast medium in the setting of primary percutaneous transluminal coronary angioplasty for AMI in the second Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) trial. Univariable and multivariable analyses were performed to assess the relation between contrast medium selection and clinical outcome (death, reinfarction, or refractory ischemia) at 30 days. Although baseline clinical and angiographic characteristics were generally similar between the 2 groups, patients who received ionic, low osmolar contrast were less likely to have been enrolled at a US site (23% vs 43%, p = 0.001) and less likely to have occlusion of the left anterior descending coronary artery (34% vs 47%, p = 0.03) or a history of prior AMI (8% vs 16%, p = 0.02). The triple composite end point of death, reinfarction, or refractory ischemia occurred less frequently in the ionic group, both in the hospital (4.4% vs 11%, p = 0.018) and at 30 days (5.5% vs 11%, p = 0.044). Although the trend favoring ionic contrast persisted, the differences were no longer statistically significant after adjustment for imbalances in baseline characteristics using a risk model developed from the study sample (n = 454, adjusted odds ratio for ionic contrast 0.48 [0.22 to 1.02], p = 0.055), and using a model developed from the entire GUSTO IIb study cohort (n = 12,142, adjusted odds ratio for ionic contrast 0.50 [0.23 to 1.06], p = 0.072). The results of this observational study warrant further elucidation by a randomized study design in this setting.