Faculty Bibliography

Antiplatelet drug therapy represents the cornerstone of treatment for cardiovascular atherothrombotic disease processes. Dual antiplatelet therapy with aspirin and oral ADP-receptor antagonists such as clopidogrel are currently the standard care for prevention of ischemic events in patients with acute coronary syndrome and who are undergoing percutaneous coronary intervention. However, despite the clinical benefit associated with clopidogrel therapy, this drug has several limitations, including a broad interindividual response variability, drug-drug interactions, slow onset of action and irreversible platelet inhibition, emphasizing the need for novel P2Y(12)-receptor antagonists. Elinogrel (PRT060128) is a reversible, potent and competitive inhibitor of the P2Y(12) receptor with a fast onset and offset of action that can be administered by both oral and intravenous routes and rapidly achieves near complete platelet inhibition. Preclinical and early-phase clinical testing have shown promising results with this novel compound, which awaits further testing in outcome-driven clinical trials. This article provides an overview of the current level of knowledge regarding elinogrel, focusing on its pharmacologic properties and preclinical and early-phase clinical development.

BACKGROUND:Measures for pay-for-performance and public reporting programs may be based on clinical practice guidelines. The impact of guideline changes over time-and whether evolving clinical evidence can render measures based on prior guidelines misleading-is not known. OBJECTIVE:To assess the impact of using different percutaneous coronary intervention (PCI) guidelines when evaluating whether PCI was indicated. RESEARCH DESIGN/METHODS:PCIs from the National Cardiovascular Data Registry's CathPCI registry performed in 2003-2004 were categorized into indication classes (Class I, IIa, IIb, III), using 2001 American College of Cardiology/American Heart Association guidelines for PCI, the guidelines available at the time of the procedures. The same procedures were recategorized using 2005 guidelines, which reflect the best evidence available to clinicians at the time of PCI. Procedures unable to be categorized were labeled as "Not Certain." SUBJECTS/METHODS:Patients undergoing PCI for stable or unstable angina in 394 hospitals. MEASURES/METHODS:Number of procedures changing classification categories using 2001 versus 2005 guidelines. RESULTS:A total of 345,779 PCIs were evaluated. Applying 2001 guidelines, 47.9% had Class I indications; 33.3% Class IIa; 5.9% Class IIb; 3.7% Class III; and 9.2% Not Certain. Applying 2005 guidelines to the same procedures, 25.1% had Class I indications; 57.5% Class IIa; 5.5% Class IIb; 3.7% Class III; and 8.3% Not Certain; 41.1% of procedures changed the classification overall. CONCLUSIONS:The changes in guidelines resulted in a marked shift in whether PCIs done in 2003-2004 were considered indicated. Guideline-based performance measures should be carefully evaluated before implementation to avoid incorrect assessments of quality of care.

CONTEXT/BACKGROUND:The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain. OBJECTIVE:To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010. INTERVENTIONS/METHODS:Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT). MAIN OUTCOME MEASURES/METHODS:Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30. RESULTS:The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15). CONCLUSION/CONCLUSIONS:Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov Identifier: NCT00790907.

OBJECTIVES/OBJECTIVE:Review the use of drug-eluting stents (DES) to evaluate changes in use. BACKGROUND:The DES were approved after several small studies in carefully selected patients showed dramatic reduction in in-stent restenosis. The DES were then rapidly adopted into routine practice. In 2006, 3 years after introduction, serious concerns regarding long-term safety were raised. METHODS:We queried the American College of Cardiology/National Cardiovascular Data Registry (ACC/NCDR) CathPCI Registry. The percentage of DES used through mid-2009 was reviewed overall and in subgroups of patients categorized by lesion type, clinical factors, insurance, and hospital characteristics. Multivariable logistic models relating these covariates to DES usage were constructed for 3 relevant time intervals. RESULTS:A total of 2,247,647 coronary stent procedures were analyzed. By 2005 over 90% of first stents placed were DES. Safety concerns arising in 2006 reduced DES use to 64% of first stent placed. After publication of salutary outcomes data in 2008, usage increased to 76% by mid-2009. The logistic models demonstrated decreased likelihood of DES usage in patients with: 1) ST-segment elevation myocardial infarctions; and 2) no medical insurance. The DES usage increased for in-stent restenosis. Hospital characteristics were not associated with significant differences in DES usage. CONCLUSIONS:There was rapid adoption of DES into U.S. clinical practice. Concern for late stent thrombosis in 2006 significantly altered DES use with reductions seen in subgroups at risk for thrombosis and patients with no insurance. These rapid cyclic changes after DES introduction reinforce the need for continuous, timely reporting of outcomes data after the introduction of new technologies.

OBJECTIVES/OBJECTIVE:The aim of this study was to evaluate practice of transradial approach (TRA). BACKGROUND:TRA has been adopted as an alternative access site for coronary procedures. METHODS:A questionnaire was distributed worldwide with Internet-based software. RESULTS:The survey was conducted from August 2009 to January 2010 among 1,107 interventional cardiologists in 75 countries. Although pre-TRA dual hand circulation testing is not uniform in the world, >85% in the U.S. perform Allen or oximetry testing. Right radial artery is used in almost 90%. Judkins catheters are the most popular for left coronary artery angiographies (66.5%) and right coronary artery angiographies (58.8%). For percutaneous coronary intervention (PCI), 6-F is now standard. For PCI of left coronary artery, operators use standard extra back-up guiding catheters in >65% and, for right coronary artery 70.4% use right Judkins catheters. Although heparin remains the routine antithrombotic agent in the world, bivalirudin is frequently used in the U.S. for PCI. The incidence of radial artery occlusion before hospital discharge is not assessed in >50%. Overall, approximately 50% responded that their TRA practice will increase in the future (68.4% in the U.S.). CONCLUSIONS:TRA is already widely used across the world. Diagnostic and guiding-catheters used for TRA remain similar to those used for traditional femoral approach, suggesting that specialized radial catheters are not frequently used. However, there is substantial variation in practice as it relates to specific aspects of TRA, suggesting that more data are needed to determine the optimal strategy to facilitate TRA and optimize radial artery patency after catheterization.

OBJECTIVES/OBJECTIVE:We examined a large registry to determine the frequency and factors associated with drug-eluting stents (DES) use in saphenous vein graft (SVG) in contemporary practice. BACKGROUND:Prospective trials comparing DES with bare-metal stents in SVG lesions have provided conflicting conclusions regarding safety and efficacy leading to potential variation in stent choice for these lesions. METHODS:We analyzed the frequency and factors associated with DES use in patients undergoing SVG stenting from January 1, 2004, to March 31, 2009, in the National Cardiovascular Data Registry. Generalized estimating equations logistic regression modeling was used to generate independent variables associated with DES use in SVGs. RESULTS:During the study period, percutaneous coronary intervention (PCI) of a SVG represented 5.7% of the total PCI volume (91,355 of 1,596,966). Of the 84,875 patients who received a SVG stent, a DES was used in 64.5%. From 2005 to 2009, DES use in SVG PCI changed from 80% to 62%. Unfractionated heparin was used in 46%, enoxaparin in 17%, bivalirudin in 42%, and a glycoprotein IIb/IIIa inhibitor in 40% of cases. On multivariable analysis, several parameters (including the period, multivessel PCI, prior PCI, no acute myocardial infarction, and no smoking) were associated with DES use. CONCLUSIONS:Currently, DES are used in nearly two-thirds of SVG interventions. Several clinical parameters (such as the period of implantation and the complexity of coronary artery disease) are associated with the decision to implant a DES in these challenging lesions.

BACKGROUND:Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells. STUDY DESIGN/METHODS:REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin α on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin α dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin α or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling. CONCLUSION/CONCLUSIONS:The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin α in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax(®), The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.

BACKGROUND:There is uncertainty regarding the optimal adjunctive unfractionated heparin (UFH) regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with fondaparinux. OBJECTIVE:The aim of this study is to evaluate the safety of 2 dose regimens of adjunctive intravenous UFH during PCI in high-risk patients with NSTE-ACS initially treated with fondaparinux and referred for early coronary angiography. DESIGN/METHODS:This is an international prospective cohort study of approximately 4,000 high-risk patients presenting to hospital with unstable angina or non-ST-segment elevation myocardial infarction, treated with fondaparinux as initial medical therapy, and referred for early coronary angiography with a view to revascularization. Within this cohort, 2,000 patients undergoing PCI will be eligible for enrollment into a double-blind international randomized parallel-group trial evaluating standard activated clotting time (ACT)-guided doses of intravenous UFH versus a non-ACT-guided weight-adjusted low dose. The standard regimen uses an 85-U/kg bolus of UFH if there is no platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitor or 60 U/kg if GpIIb-IIIa inhibitor use is planned, with additional bolus guided by blinded ACT measurements. The low-dose regimen uses a 50 U/kg UFH bolus, irrespective of planned GpIIb-IIIa use. The primary outcome is the composite of peri-PCI major bleeding, minor bleeding, or major vascular access site complications. The assessment of net clinical benefit is a key secondary outcome: it addresses the composite of peri-PCI major bleeding with death, myocardial infarction, or target vessel revascularization at day 30. CONCLUSION/CONCLUSIONS:FUTURA/OASIS 8 will help define the optimal UFH regimen as adjunct to PCI in high-risk NSTE-ACS patients treated with fondaparinux.