A. Michael Lincoff

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction)

Angina/Non-ST-Elevation Myocardial Infarction : ACC/AHA 2007 Guidelines for the Management of Patients With Unstable ISSN: 1524-4539 Copyright

Predictors of Outcome in Patients With Acute Coronary Syndromes Without Persistent ST-Segment Elevation Results From an International Trial of 9461 Patients

BACKGROUND Appropriate treatment policies should include an accurate estimate of a patients baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation. METHODS AND RESULTS We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted chi(2)=95), heart rate (chi(2)=32), systolic blood pressure (chi(2)=20), ST-segment depression (chi(2)=20), signs of heart failure (chi(2)=18), and cardiac enzymes (chi(2)=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (chi(2)=21) than of death alone (chi(2)=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81). CONCLUSIONS The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process.

Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries

BACKGROUND With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery. METHODS AND RESULTS Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/ PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90 degrees of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79 +/- 0.22, 1.12 +/- 0.01, 2.36 +/- 0.60, 1.24 +/- 0.36, and 1.43 +/- 0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46 +/- 0.18 and 0.61 +/- 0.23 mm, respectively) and for the nonbiodegradable PETP (0.46 +/- 0.11 mm). CONCLUSIONS An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.

Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes: The PERISCOPE Randomized Controlled Trial

CONTEXT No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. OBJECTIVE To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. INTERVENTIONS A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. MAIN OUTCOME MEASURE Change in percent atheroma volume (PAV) from baseline to study completion. RESULTS Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. CONCLUSION In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00225277.

2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable Angina/non-ST-elevation myocardial infarction: A report of the American College of cardiology foundation/American heart association task force on practice guidelines

Developed in Collaboration With the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency

Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes

BACKGROUND Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Intravenous Platelet Blockade with Cangrelor during PCI

BACKGROUND Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI). METHODS In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point. RESULTS The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas. CONCLUSIONS The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

Platelet inhibition with cangrelor in patients undergoing PCI

BACKGROUND Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition. METHODS We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. RESULTS We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14). CONCLUSIONS Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.)

Cell adhesion molecules in coronary artery disease.

To date, six families of cell adhesion molecules are known. These are cell surface receptors that mediate adhesion of cells to each other or to components of the extracellular matrix and include integrins, selectins, the immunoglobulin superfamily, cadherins, proteoglycans and mucins. These cell adhesion molecules play a key role in cell-cell interaction (such as among endothelium, monocytes, smooth muscle cells and platelets) and cell-extracellular matrix interaction (such as between leukocytes, platelets or fibroblasts and the extracellular matrix). The importance of these interactions has recently been demonstrated in clinical trials with the use of an antibody fragment directed against the platelet alpha IIb beta IIIa integrin, with reduction of arterial thrombosis and restenosis after percutaneous coronary interventions. A fundamental role for cell adhesion molecules has been suggested for several other relevant disease processes, including atherosclerosis, acute coronary syndromes, reperfusion injury and allograft vasculopathy. This review focuses on providing the clinically relevant biology of these families of adhesion molecules, setting the foundation for delineation of their emerging role in cardiovascular therapeutics.

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.