Faculty Bibliography

The use of glycoprotein IIb/IIIa inhibitors (GPI) reduces ischemic events in patients undergoing percutaneous coronary intervention (PCI). However, the same properties that confer this benefit lead to an increased bleeding risk. Recent studies have shown a less robust net clinical benefit of GPI in the current era of routine thienopyridine and direct thrombin inhibitor use. To optimize the net clinical benefit of GPI, these agents need to be selectively used in patients most likely to benefit from their anti-ischemic effect, namely patients undergoing PCI for non-ST-segment elevation myocardial infarction, select patients undergoing primary PCI, and select patients undergoing PCI without appropriate pre-loading with a thienopyridine. Moreover, strategies to minimize bleeding should be applied in these patients and include shorter GPI infusions (in some patients), dose adjustments of heparin and GPI, careful access site management with more frequent use of the transradial approach, use of smaller sheaths, and identification of patients at high bleeding risk. This review provides an update of the current literature that supports these measures, an insight on the tailored use of GPI, and a potential direction for future research addressing combined antithrombotic therapies.

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.

Coronary artery plaque rupture results in platelet adhesion and activation, the release of adenosine diphosphate (ADP), thromboxane A(2), and the generation of thrombin. These factors propagate further platelet activation through a positive feedback mechanism, resulting in the formation of a platelet plug. The treatment of patients with ACS is centered upon the prompt initiation of both antiplatelet and anticoagulant agents. The widespread use of antiplatelet and anticoagulant agents has resulted in a significant reduction in morbidity and mortality but has also increased the risk for bleeding complications. Female gender, advanced age, low body mass index (BMI), low creatinine clearance, and the use of percutaneous coronary intervention have been consistently shown to be risk factors for bleeding. While bleeding was thought to be a necessary side effect and of little clinical significance in the past, it is now clear that bleeding is an independent predictor of adverse ischemic events and mortality. The mechanisms underlying this relationship are not yet fully elucidated and are likely multifactorial (direct effects of bleeding, increased incidence of blood transfusions, less use of antiplatelet agents in both the short and long term). Current treatment guidelines for the use of antithrombotic therapy recommend utilization of evidence-based therapies using clinical strategies shown to minimize the risk of bleeding should when possible. Novel therapies that minimize bleeding risk while providing protection against thrombotic events are needed and may improve outcomes among patients with ACS. Multiple platelet activation pathways and the coagulation cascade regulate hemostasis and thrombosis. Current antiplatelet and anticoagulant therapies for acute coronary syndromes (ACS) act on distinct sites in the pathways for platelet activation and coagulation. While these therapies are effective in reducing the morbidity and mortality associated with ACS, they are associated with a clinically significant increase in the risk of bleeding events. Novel therapies that minimize bleeding risk while providing protection against thrombotic events may improve outcomes in patients with ACS.

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:Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial. METHODS:Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI. RESULTS:Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11). CONCLUSIONS:Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.

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.

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.

BACKGROUND:Although bivalirudin compared with unfractionated heparin with glycoprotein IIb/IIIa inhibitors reduces bleeding and hospitalization costs in patients undergoing percutaneous coronary intervention (PCI), little is known about the economic impact of bivalirudin versus heparin alone and at what threshold of procedural bleeding risk bivalirudin would be considered cost-effective. METHODS AND RESULTS/RESULTS:A validated model was used to predict risk of major bleeding for 81,628 National Cardiovascular Data Registry (NCDR) CathPCI Registry patients from 2004 to 2006 who received unfractionated heparin only. Costs were derived from multiple sources including wholesale acquisition costs (for drugs) and single-center data (for PCI-related complications). Based on ISAR-REACT 3, we assumed that bivalirudin would reduce the risk of major bleeding by 33% compared with unfractionated heparin alone. A Markov model was used to estimate lost life expectancy associated with a major bleed. Major bleeding was predicted to occur in 2.2% of patients. Bivalirudin for all patients was estimated to increase costs by $571 per patient, yielding cost-effectiveness ratios of $287,473 per bleeding event averted and $1,173,360 per quality-adjusted life-year gained. Bivalirudin was cost saving for patients with a predicted bleeding risk >20% (0.16% of CathPCI population). At willingness-to-pay thresholds of $50K and $100K per quality-adjusted life-year gained, bivalirudin was cost-effective for patients with a bleeding risk > or = 8% (2.5% patients) and > or = 5% (7.9% patients), respectively. CONCLUSIONS:This decision-analytic modeling study demonstrates that for patients undergoing PCI, substitution of bivalirudin for unfractionated heparin monotherapy is projected to increase costs for virtually all patients and would be considered cost-effective for only a minority of patients with a high bleeding risk. From a policy standpoint, studies such as this, aimed at identifying the appropriate risk threshold for initiating treatment, may help in the development of informed guidelines for the use of expensive therapies.