Coronary Artery Disease: Harrington RA

Becker RC, Meade TW, Berger PB, Ezekowitz M, O'Connor CM, Vorchheimer DA, Guyatt GH, Mark DB, Harrington RA, Anonymous00140. · Duke Cardiovascular Thrombosis Center, Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705, USA. · Chest. · Pubmed #18574278 links to  free full text

Abstract: The following chapter devoted to antithrombotic therapy for chronic coronary artery disease (CAD) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation" chapter by Guyatt et al in this supplement, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with non-ST-segment elevation (NSTE)-acute coronary syndrome (ACS) we recommend daily oral aspirin (75-100 mg) [Grade 1A]. For patients with an aspirin allergy, we recommend clopidogrel, 75 mg/d (Grade 1A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we suggest discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients after myocardial infarction, after ACS, and those with stable CAD and patients after percutaneous coronary intervention (PCI), we recommend daily aspirin (75-100 mg) as indefinite therapy (Grade 1A). We recommend clopidogrel in combination with aspirin for patients experiencing ST-segment elevation (STE) and NSTE-ACS (Grade 1A). For patients with contraindications to aspirin, we recommend clopidogrel as monotherapy (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend aspirin (75 to 100 mg/d) [Grade 1B]. For patients who undergo bare metal stent placement, we recommend the combination of aspirin and clopidogrel for at least 4 weeks (Grade 1A). We recommend that patients receiving drug-eluting stents (DES) receive aspirin (325 mg/d for 3 months followed by 75-100 mg/d) and clopidogrel 75 mg/d for a minimum of 12 months (Grade 2B). For primary prevention in patients with moderate risk for a coronary event, we recommend aspirin, 75-100 mg/d, over either no antithrombotic therapy or vitamin K antagonist (Grade 1A).

Harrington RA, Becker RC, Cannon CP, Gutterman D, Lincoff AM, Popma JJ, Steg G, Guyatt GH, Goodman SG, Anonymous00138. · Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705, USA. · Chest. · Pubmed #18574276 links to  free full text

Abstract: This chapter about antithrombotic therapy for coronary artery disease is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicans Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggestions are weaker as there is uncertainty regarding the benefits, risks and costs such that individual patients' values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation for Antithrombotic Agents" chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations are the following: for all patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), without a clear allergy to aspirin, we recommend immediate aspirin (162 to 325 mg po) and then daily oral aspirin (75 to 100 mg) [Grade 1A]. For NSTE ACS patients who are at at least moderate risk for an ischemic event and who will undergo an early invasive management strategy, we recommend "upstream" treatment either with clopidogrel (300 mg po bolus, followed by 75 mg/d) or a small-molecule IV glycoprotein (GP) IIb/IIIa inhibitor (eptifibatide or tirofiban) [Grade 1A]. For NSTE ACS patients who are at least moderate risk for an ischemic event and for whom an early conservative or a delayed invasive strategy of management is to be used, we recommend "upstream" treatment with clopidogrel (300 mg oral bolus, followed by 75 mg/d) [Grade 1A]. For NSTE ACS patients who undergo PCI, we recommend treatment with both clopidogrel and an IV GP IIb/IIIa inhibitor (Grade 1A). We recommend a loading dose of 600 mg of clopidogrel given at least 2 h prior to planned PCI followed by 75 mg/d (Grade 1B). For all patients presenting with NSTE ACS, we recommend anticoagulation with UFH or LMWH or bivalirudin or fondaparinux over no anticoagulation (Grade 1A). For NSTE ACS patients who will undergo an early invasive strategy of management, we recommend UFH (with a GP IIb/IIIa inhibitor) over either LMWH or fondaparinux (Grade 1B). For NSTE ACS patients in whom an early conservative or a delayed invasive strategy of management is to be used, we recommend fondaparinux over enoxaparin (Grade 1A) and LMWH over UFH (Grade 1B). We recommend continuing LMWH during PCI treatment of patients with NSTE ACS when it has been started as the "upstream" anticoagulant (Grade 1B). In low- to moderate-risk patients with NSTE ACS undergoing PCI, we recommend either bivalirudin with provisional ("bail-out") GP IIb/IIIa inhibitors or UFH plus a GP IIb/IIIa inhibitor over alternative antithrombotic regimens (Grade 1B).

Harrington RA, Becker RC, Ezekowitz M, Meade TW, O'Connor CM, Vorchheimer DA, Guyatt GH. · Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705, USA. · Chest. · Pubmed #15383483 links to  free full text

Abstract: This chapter about antithrombotic therapy for coronary artery disease (CAD) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), we recommend immediate and then daily oral aspirin (Grade 1A). For patients with an aspirin allergy, we recommend immediate treatment with clopidogrel, 300-mg bolus po, followed by 75 mg/d indefinitely (Grade 1A). In all NSTE ACS patients in whom diagnostic catheterization will be delayed or when coronary bypass surgery will not occur until > 5 days, we recommend clopidogrel as bolus therapy (300 mg), followed by 75 mg/d for 9 to 12 months in addition to aspirin (Grade 1A). In NSTE ACS patients in whom angiography will take place within 24 h, we suggest beginning clopidogrel after the coronary anatomy has been determined (Grade 2A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). In moderate- to high-risk patients presenting with NSTE ACS, we recommend either eptifibatide or tirofiban for initial (early) treatment in addition to treatment with aspirin and heparin (Grade 1A). For the acute treatment of NSTE ACS, we recommend low molecular weight heparins over unfractionated heparin (UFH) [Grade 1B] and UFH over no heparin therapy use with antiplatelet therapies (Grade 1A). We recommend against the direct thrombin inhibitors as routine initial antithrombin therapy (Grade 1B). For patients after myocardial infarction, after ACS, and with stable CAD, we recommend aspirin in doses from 75 to 325 mg as initial therapy and in doses of 75 to 162 mg as indefinite therapy (Grade 1A). For patients with contraindications to aspirin, we recommend long-term clopidogrel (Grade 1A). For primary prevention in patients with at least moderate risk for a coronary event, we recommend aspirin, 75 to 162 mg/d, over either no antithrombotic therapy or vitamin K antagonist (VKA) [Grade 2A]; for patients at particularly high risk of events in whom the international normalized ratio (INR) can be monitored without difficulty, we suggest low-dose VKA (target INR, 1.5) [Grade 2A].

Petersen JL, Harrington RA. · No affiliation provided · Am Heart J. · Pubmed #15846254 No free full text.

This publication has no abstract.

Harrington RA. · Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina 27705, USA. · Semin Thromb Hemost. · Pubmed #15630670 No free full text.

Abstract: Platelet-dependent thrombosis is an important part of the pathophysiology of both percutaneous coronary interventions (PCI) and acute coronary syndrome (ACS). Data support the use of acute therapies that interfere with platelets to provide clinical benefit to patients presenting with acute cardiovascular disease. The discovery of platelet glycoprotein (GP) IIb/IIIa receptor antagonists has been a major advance in the pharmacotherapy for patients undergoing PCI and those presenting with ACS without ST-segment elevation. This article will cover the role of platelets in acute cardiovascular disease, as well as the discovery and development of the platelet GPIIb/IIIa inhibitors. The major focus of this article will be on examining key lessons from the trials in each of these areas as well as presenting a series of questions that still require answers from either ongoing or future research.

Becker RC, Alexander J, Dyke CK, Harrington RA. · Cardiovascular Thrombosis Center, Duke University Medical Center, Durham, NC 27715, USA. · Thromb Haemost. · Pubmed #15583722 No free full text.

Abstract: The development of anticoagulants for treating patients with atherothrombotic disorders of the arterial circulatory system has focused, either directly or indirectly, on thrombin - a pleuripotential effector enzyme with prothrombotic and proinflammatory properties. The pivotal role of factor (f) Xa in thrombin generation, coupled with its direct cellular effects and widely recognized limitations of currently available anticoagulants, has led to the development of pharmacologic inhibitors of this important protease. The following review focuses on DX-9065a - first in a class of direct, selective and reversible fXa antagonists - and its potential applications in the management of patients with cardiovascular disease.

Rebeiz AG, Roe MT, Alexander JH, Mahaffey KW, Granger CB, Peterson ED, Califf RM, Harrington RA. · Duke Clinical Research Institute and Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27715, USA. · Am J Med. · Pubmed #14715326 No free full text.

Abstract: Non-ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the growing number of pharmacologic agents makes early management of non-ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization.

Tolleson TR, Harrington RA. · Duke University Medical Center, Durham, North Carolina 27710, USA. · Curr Opin Cardiol. · Pubmed #10500902 No free full text.

Abstract: Acute coronary occlusion is a serious manifestation of coronary artery disease leading to significant short- and long-term morbidity and mortality. Traditionally classified as Q-wave myocardial infarction, non-Q-wave myocardial infarction, and unstable angina, these events are more appropriately termed acute coronary syndromes with and without ST-segment elevation, reflecting the diagnostic criteria used by clinicians to guide initial treatment strategies. Standard therapy with aspirin and heparin has been expanded with the low molecular weight heparin enoxaparin and the intravenous glycoprotein IIb/IIIa inhibitors eptifibatide and tirofiban. Debate continues as to whether a strategy of early intervention or initial conservative management is most appropriate. Continued clinical trials will help define optimal treatment strategies in this high-risk group of patients.

Chan MY, Cohen MG, Dyke CK, Myles SK, Aberle LG, Lin M, Walder J, Steinhubl SR, Gilchrist IC, Kleiman NS, Vorchheimer DA, Chronos N, Melloni C, Alexander JH, Harrington RA, Tonkens RM, Becker RC, Rusconi CP. · Duke Clinical Research Institute, 2400 Pratt St, Terrace Level Room 0311, Durham, NC 27705, USA. · Circulation. · Pubmed #18506005 links to  free full text

Abstract: BACKGROUND: Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity. METHODS AND RESULTS: We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred. CONCLUSIONS: This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

Mehta RH, Alexander JH, Emery R, Ellis SJ, Hasselblad V, Khalil A, Carrier M, Harrington RA, Tardif JC, Anonymous00428. · Duke Clinical Research Institute, Durham, NC 27715, USA. · Am Heart J. · Pubmed #18371465 No free full text.

Abstract: BACKGROUND: Coronary artery bypass graft (CABG) surgery is effective in relieving angina and improving survival and quality of life in patients with obstructive coronary artery disease; however, recurrent angina, myocardial infarction, neurological injury, and death can occur in the perioperative and postoperative period. MC-1 (pyridoxal 5'-phosphate) is a novel agent that has shown promise in reducing myocardial necrosis by reducing cellular calcium overload after percutaneous coronary intervention and CABG surgery in high-risk patients undergoing these procedures. METHODS: MEND-CABG II is a phase III study evaluating the efficacy and safety of MC-1 in reducing cardiovascular morbidity and mortality after CABG. High-risk patients undergoing CABG surgery will be randomly assigned to receive either MC-1 (250 mg/d) or matching placebo immediately before and continuing for 30 days after the procedure. The primary end point is the occurrence of cardiovascular death or nonfatal myocardial infarction through postoperative day 30. A total of 3023 patients were enrolled at 130 sites in Canada, the United States, and Germany between October 2006 and September 2007, with results anticipated shortly after completion of 90-day follow-up in March 2008. CONCLUSIONS: The data from the MEND-CABG II trial will establish whether peri- and postoperative treatment with MC-1 can decrease the short- and intermediate-term morbidity and mortality of high-risk patients undergoing CABG surgery.

Magee MJ, Alexander JH, Hafley G, Ferguson TB, Gibson CM, Harrington RA, Peterson ED, Califf RM, Kouchoukos NT, Herbert MA, Mack MJ, Anonymous00006. · Cardiopulmonary Research Science and Technology Institute, Dallas, Texas, USA. · Ann Thorac Surg. · Pubmed #18222251 No free full text.

Abstract: BACKGROUND: This analysis compares 1-year vein graft patency and major adverse cardiac and cerebral events (MACCE [death, myocardial infarction, or stroke]) in on-pump and off-pump patients enrolled in PREVENT IV (the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV). METHODS: The PREVENT IV was a multicenter (107 sites) randomized trial of edifoligide to prevent vein graft failure from neointimal hyperplasia in 3,014 patients undergoing primary, isolated coronary artery bypass grafting (CABG) with at least two vein grafts. One-year angiographic follow-up was completed on 1,920 patients (4,736 grafts) with MACCE follow-up on 99.4% of enrolled patients. RESULTS: In all, 2,377 procedures (78.9%) were on pump and 637 (21.1%) were off pump. On-pump patients had more chronic lung disease (17% versus 11%; p < 0.001), congestive heart failure (10% versus 7%; p = 0.03), lower mean ejection fraction (50% versus 55%; p < 0.001), and worse target artery quality (good 63.8% versus 68.1%; fair 26.4% versus 22.7%; poor 9.8% versus 9.2%; p < 0.001). Vein graft failure (more than 75% graft stenosis) in on- versus off-pump patients was 25.3% versus 25.7% (p = 0.62). After adjusting for differences in significant predictors of vein graft failure (target artery quality, surgery time, endoscopic vein harvest, more than 1 distal anastomosis/graft, and patient weight), the odds of vein graft failure was 0.82 (95% confidence interval: 0.67 to 1.00; p = 0.05) for on-pump versus off-pump patients. One-year mortality for on- versus off-pump patients was 3.3% versus 2.5% (p = 0.30); and MACCE was 15.4% versus 11.3% (p = 0.01). The adjusted hazard ratio for 1-year MACCE was 1.31 (95% confidence interval: 1.01-1.69; p = 0.01) for on pump versus off pump. CONCLUSIONS: Observed saphenous vein failure rate was 25% in both groups. One-year clinical outcomes (MACCE) were better with off-pump than with on-pump CABG, suggesting benefits not related to vein graft patency.

Dyke CK, Steinhubl SR, Kleiman NS, Cannon RO, Aberle LG, Lin M, Myles SK, Melloni C, Harrington RA, Alexander JH, Becker RC, Rusconi CP. · Duke Clinical Research Institute, Durham, NC 27715, USA. · Circulation. · Pubmed #17101847 links to  free full text

Abstract: BACKGROUND: Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study. METHODS AND RESULTS: Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline. CONCLUSIONS: These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

Gurm HS, Sarembock IJ, Kereiakes DJ, Young JJ, Harrington RA, Kleiman N, Feit F, Wolski K, Bittl JA, Wilcox R, Topol EJ, Lincoff AM. · Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · J Am Coll Cardiol. · Pubmed #15963389 No free full text.

Abstract: OBJECTIVES: The objective of this study was to confirm that the efficacy and safety of percutaneous coronary intervention (PCI) in diabetic patients are not compromised by a bivalirudin-based antithrombotic strategy. BACKGROUND: Previous studies have shown a survival benefit with use of platelet glycoprotein (GP) IIb/IIIa inhibitors in diabetic patients undergoing PCI. The Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial showed the non-inferiority of a strategy of bivalirudin with provisional GP IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. The relative efficacy of these two strategies in diabetic patients has not been studied. METHODS: We evaluated the diabetic patients enrolled in the REPLACE-2 trial to assess the impact of these antithrombotic strategies on the short- and long-term outcome after PCI. RESULTS: The REPLACE-2 trial enrolled 1,624 diabetic patients and 4,368 non-diabetic patients. Compared with non-diabetic patients, diabetic patients had similar short-term outcome but higher mortality at 1 year (3.06% vs. 1.85%, p = 0.004). There was no difference in short-term or long-term ischemic events among the diabetic patients randomized to the two arms. Specifically, the 1-year mortality rate was non-significantly lower in the bivalirudin arm, suggesting no differential survival impact of the two strategies (2.3% vs. 3.9%). There was less minor bleeding in the bivalirudin arm in diabetic patients (12.6% vs. 24.4%, p < 0.001), whereas no difference was seen in the incidence of major bleeding (3.0% vs. 3.3%, p = 0.69). CONCLUSIONS: Compared with routine GP IIb/IIIa inhibition, the use of bivalirudin with provisional GP IIb/IIIa inhibitors in diabetic patients is associated with no differences in clinical outcomes at 30 days, a trend toward lesser mortality at 1 year, and a reduction in minor bleeding.

Alexander JH, Yang H, Becker RC, Kodama K, Goodman S, Dyke CK, Kleiman NS, Hochman JS, Berger PB, Cohen EA, Lincoff AM, Burton JR, Bovill EG, Kawai C, Armstrong PW, Harrington RA, Anonymous00289. · Duke University Center and Duke Clinical Research Institute, Durham, NC 27715, USA. · J Thromb Haemost. · Pubmed #15748230 No free full text.

Abstract: 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.

Ferguson JJ, Antman EM, Bates ER, Cohen M, Every NR, Harrington RA, Pepine CJ, Theroux P, Anonymous00056. · Cardiology Research 1-191, St Luke's Episcopal Hospital, Houston, Tex 77225, USA. · Am Heart J. · Pubmed #14564315 No free full text.

Abstract: BACKGROUND: In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI). METHODS: The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non-ST-elevation ACS. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia. RESULTS: A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively). CONCLUSIONS: The safety of enoxaparin plus a GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus a GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.

Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graffagnino C, Davis S, Diener HC, Ferguson J, Fitzgerald D, Granett J, Shuaib A, Koudstaal PJ, Theroux P, Van de Werf F, Sigmon K, Pieper K, Vallee M, Willerson JT, Anonymous00048. · Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Circulation. · Pubmed #12874182 links to  free full text

Abstract: BACKGROUND: This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. METHODS AND RESULTS: Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban. CONCLUSIONS: Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Tolleson TR, O'Shea JC, Bittl JA, Hillegass WB, Williams KA, Levine G, Harrington RA, Tcheng JE. · Duke University Medical Center and Clinical Research Institute, Durham, NC 27705, USA. · J Am Coll Cardiol. · Pubmed #12575964 No free full text.

Abstract: OBJECTIVES: We evaluated the relationship between the degree of heparin anticoagulation and clinical efficacy and bleeding in patients undergoing contemporary percutaneous coronary intervention (PCI) with stent implantation. BACKGROUND: Despite universal acceptance of heparin anticoagulation as a standard of care in PCI, considerable controversy still exists regarding the appropriate dosing of heparin. METHODS: The study population (n = 2,064) comprised all patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. The index activated clotting time (ACT) was defined as the ACT measured after the last heparin dose and before first device activation and was correlated with outcome and bleeding events. RESULTS: No association was observed between decreasing ACT levels and the rate of ischemic events in the treatment or placebo arms. The incidence of the primary composite end point (death, myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy at 48 h) was actually lowest in the lowest ACT tertile for both the placebo (10.0%) and treatment groups (6.1%). When analyzed by tertile, major bleeding rates did not increase in the lowest ACT tertile in patients given placebo (0.6%) versus those receiving eptifibatide (0.7%). Major bleeding rates increased as the ACT increased in the eptifibatide-treated patients. CONCLUSIONS: Ischemic end points in patients undergoing contemporary PCI with stent placement do not increase by decreasing ACT levels, at least to a level of 200 s. Bleeding events do increase with increasing ACT levels and are enhanced with eptifibatide treatment. An ACT of 200 to 250 s is reasonable in terms of efficacy and safety with the use of contemporary technology and pharmacotherapy.

Breeman A, Mercado N, Lenzen M, van den Brand MM, Harrington RA, Califf RM, Topol EJ, Simoons ML, Boersma E, Anonymous00022. · Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands. · Cardiology. · Pubmed #12566649 No free full text.

Abstract: BACKGROUND: The 6-month clinical outcome of patients with multivessel disease enrolled in PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) is described. Patients with complete angiography data were included; multivessel disease was stratified according to the treatment strategy applied early during hospitalization, i.e. medical treatment, percutaneous coronary intervention (PCI) (balloon), PCI (stent), or coronary artery bypass grafting (CABG). METHODS: Patients were divided into three groups according to the treatment strategy applied during the first 30 days of enrolment. Patients who did not undergo a percutaneous or surgical coronary intervention were classified as medically treated. Patients who underwent a PCI (prior to a possible CABG) were separated from those who underwent a CABG (prior to a possible PCI). The PCI group was further subdivided: patients receiving >/=1 coronary stents were separated from those in whom no stents were used. RESULTS: The mortality rate at 30 days was 6.7, 3.9, 2.4 and 4.8% for the medical treatment, PCI (balloon), PCI (stent) and CABG groups, respectively (p value = 0.002). Differences as observed at 30 days were still present at 6-month follow-up with 11.1, 5.8, 5.5 and 6.5% mortality event rates for the aforementioned groups (p value = 0.002). The 30-day myocardial infarction (MI) rate according to the opinion of the Clinical Events Committee was lower among medically than non-medically treated patients, with the highest event rate observed in the CABG group (27.7%). Approximately half of the MIs in the PCI and CABG subgroups occurred within 48 h after the procedure. CONCLUSIONS: The observed differences in clinical outcomes are explained by an imbalance in baseline characteristics and comorbid conditions between the analyzed groups of patients.

Labinaz M, Kilaru R, Pieper K, Marso SP, Kitt MM, Simoons ML, Califf RM, Topol EJ, Armstrong PW, Harrington RA. · University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Circulation. · Pubmed #11804987 links to  free full text

Abstract: BACKGROUND: Patients with prior CABG with a subsequent non-ST-segment elevation acute coronary syndrome (ACS) pose an increasingly important clinical problem. Although GP IIb/IIIa inhibitors have improved the outcome of patients with ACS, their efficacy in patients with prior CABG has not been previously evaluated. Methods and Results- We analyzed the 30- and 180-day outcomes of patients with prior CABG enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. In this trial, which evaluated the efficacy of eptifibatide in patients with ACS, 1134 patients (12%) with prior CABG and 8321 without prior CABG were enrolled. After adjusting for differences in baseline characteristics and treatment, patients with prior CABG had a significantly higher mortality rates at 30 days (hazard ratio [HR], 1.45 [95% CI, 1.06 to 1.98]; P=0.019) and at 180 days (HR, 1.32 [95% CI, 1.04 to 1.67]; P=0.021). At 30 days, there was a similar effect on the primary end point of death or myocardial infarction in the eptifibatide group versus the placebo group in prior CABG patients (unadjusted HR, 0.90 [95% CI, 0.67 to 1.20]) and in patients without a history of CABG (unadjusted HR, 0.89 [95% CI, 0.80 to 0.99]). CONCLUSIONS: Patients with prior CABG with non-ST-segment elevation ACS have a significantly worse prognosis than do patients without a history of CABG. The treatment effect of eptifibatide in the prior CABG group was similar to the effect seen in patients without prior CABG.

Marso SP, Bhatt DL, Roe MT, Houghtaling PL, Labinaz M, Kleiman NS, Dyke C, Simmoons ML, Califf RM, Harrington RA, Topol EJ. · Mid America Heart Institute, Saint Luke's Hospital, Kansas City, MO 64111, USA. · Circulation. · Pubmed #11113045 links to  free full text

Abstract: BACKGROUND: Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown. METHODS AND RESULTS: The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7). CONCLUSIONS: Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

Hasdai D, Holmes DR, Criger DA, Topol EJ, Califf RM, Wilcox RG, Paolasso E, Simoons M, Deckers J, Harrington RA. · Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel. · Am Heart J. · Pubmed #10689260 No free full text.

Abstract: BACKGROUND: Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers. METHODS: The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain </=24 hours and having either ischemic electrocardiographic changes without persistent ST-segment elevation or elevated creatine kinase MB levels. Patients were randomly assigned to receive a bolus and infusion of either eptifibatide or placebo in addition to standard therapy. The primary end point was a composite of death or nonfatal myocardial infarction within 30 days. RESULTS: Of the 9406 patients with known smoking status, 2677 were current smokers, 3086 were former smokers, and 3643 were nonsmokers. Cigarette smokers had better 30-day outcomes (12.3%, 16.8%, and 15.4% for smokers, former smokers, and nonsmokers, respectively; P =.001). However, after adjusting for differences in baseline clinical variables, smoking status was not a predictor of 30-day outcome (P =.45). There was a reduction in the composite end point overall with eptifibatide compared with placebo (14.3% vs 15. 7%, P =.054) but no interaction between smoking status and treatment strategy (P =.68). CONCLUSIONS: Among patients with ACS without persistent ST-segment elevation, cigarette smokers had better short-term outcomes because of their more favorable clinical profile. Although prior studies have suggested that smokers more commonly have platelet-rich thrombi than nonsmokers, eptifibatide did not result in more improvement in their outcome compared with former smokers or nonsmokers.

Bhatt DL, Peterson ED, Harrington RA, Ou FS, Cannon CP, Gibson CM, Kleiman NS, Brindis RG, Peacock WF, Brener SJ, Menon V, Smith SC, Pollack CV, Gibler WB, Ohman EM, Roe MT, Anonymous00072. · VA Boston Healthcare System and Brigham and Women's Hospital, Boston, MA, USA. · Eur Heart J. · Pubmed #19339264 No free full text.

Abstract: AIMS: The presence of peripheral arterial disease (PAD) or cerebrovascular disease (CVD) is associated with higher likelihood of significant coronary artery disease (CAD). We sought to assess the prevalence of PAD, CVD, prior CAD, or pre-existent disease in multiple arterial territories ('polyvascular' disease) in patients presenting with non-ST-segment elevation acute coronary syndrome and its impact on adverse events. METHODS AND RESULTS: Data from 95 749 patients enrolled from February 2003 to September 2006 at 484 sites in the CRUSADE registry were analysed. Patients were categorized as having prior 0, 1, 2, or 3 affected arterial beds. The rates of in-hospital mortality, myocardial infarction, stroke, and congestive heart failure were analysed, as were the rates of non-bypass surgery-related red blood cell transfusion and major bleeding. On presentation, 11,345 (11.9%) patients had established PAD, 9973 (10.4%) had documented CVD, and 41,404 (43.2%) had prior CAD. In this cohort, 0, 1, 2, and 3 arterial bed disease before presentation was present in 46 814 (48.9%, 95% CI 48.6-49.2%), 36 704 (38.3%, 95% CI 37.8-39.0%), 10 675 (11.2%, 95% CI 10.9-11.9%), and 1556 (1.6%, 95% CI 1.5-1.8%) patients, respectively. The rates of ischaemic events increased with the number of affected vascular beds. The adjusted odds ratio for the composite of in-hospital ischaemic events for pre-existent disease in 1, 2, or 3 arterial beds (compared with 0 arterial bed involvement) increased from 1.07 to 1.26 to 1.31 (P < 0.001). Similarly, the adjusted odds ratio for transfusion increased with greater disease burden from 1.11 to 1.28 to 1.30 (P < 0.001), although the adjusted rates of protocol-defined non-bypass surgery-related major bleeding did not. CONCLUSION: Prior polyvascular disease increases the risk of in-hospital adverse events, including mortality. Identification of these patients in clinical trial and real world populations may provide an opportunity to reduce their excess risk with intensive secondary prevention efforts.

Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, Sisk CM, Strony J, Musliner TA, McCabe CH, Veltri E, Braunwald E, Califf RM, Anonymous00021. · The TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. · Am Heart J. · Pubmed #19061694 No free full text.

Abstract: BACKGROUND: Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes (ACSs). The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a multicenter, randomized, double-blind, active-control trial designed to test the hypothesis that the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS. STUDY DESIGN: The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS. Patients are randomized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg. Follow-up visits are at 1 and 4 months, and every 4 months thereafter. If consecutive measures of LDL-C are >79 mg/dL at follow-up visits, the simvastatin dose will be increased to 80 mg in a double-blind manner. The primary end point is the first occurrence of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke. Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point. SUMMARY: IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS. In addition, the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further.

Anstrom KJ, Kong DF, Shaw LK, Califf RM, Kramer JM, Peterson ED, Rao SV, Matchar DB, Mark DB, Harrington RA, Eisenstein EL. · Department of Biostatistics, Duke Clinical Research Institute, Durham, NC 27715, USA. · Arch Intern Med. · Pubmed #18695078 No free full text.

Abstract: BACKGROUND: Clinical trials of drug-eluting stents (DES) vs bare metal stents (BMS) report a reduced need for target lesion revascularization with no difference in death or myocardial infarction. However, these trials selectively enrolled patients with lower risk, single-vessel coronary artery disease (CAD) and limited the follow-up period to 1 year or less. Thus, it is not known how these short-term results apply to patients with higher risk, multivessel CAD seen in community practice settings. The objective of this study was to compare the long-term clinical outcomes of patients receiving DES vs BMS in a clinical practice setting. METHODS: Patients from the Duke Databank for Cardiovascular Disease undergoing their initial revascularization with DES or BMS from January 1, 2000, through July 31, 2005, were included in the study population. Propensity scores and inverse probability weighted estimators were used to adjust for treatment group imbalances. RESULTS: The study population included 1501 patients who received DES and 3165 who received BMS. After adjustment, DES reduced target vessel revascularization (TVR) rates at 6, 12, and 24 months compared with BMS (24-month rates: DES, 6.6%; BMS, 16.3%; difference, -9.7%; 95% confidence interval [CI], -11.7% to -7.7%; P < .001). The TVR benefit for DES increased among patients with multivessel CAD (1-vessel CAD: -8.3%; 95% CI, -10.9% to -5.8%; P < .001; 2-vessel CAD: -9.7%; 95% CI, -3.6% to -5.8%; P < .001; 3-vessel CAD: -16.2%; 95% CI, -25.2% to -7.2%; P < .001). However, in the overall cohort there were no statistically significant differences in the composite of death or myocardial infarction. CONCLUSIONS: Patients receiving DES vs BMS in a clinical practice setting have lower TVR rates, albeit with less absolute benefit than those observed in clinical trials. Patients with multivessel vs single-vessel disease experience a greater reduction in TVR.

Leung S, Gallup D, Mahaffey KW, Cohen M, Antman EM, Goodman SG, Harrington RA, Langer A, Aylward P, Ferguson JJ, Califf RM, Anonymous00272. · University of Kentucky, Lexington, KY, USA. · Am Heart J. · Pubmed #18585514 No free full text.

Abstract: BACKGROUND: Smoking remains a major public health issue. We investigated the incidence of smoking and outcomes in high-risk patients with acute coronary syndromes. Differences in treatment effect of antithrombin therapies were also investigated. METHODS: Using data from SYNERGY, patients were categorized by their self-reported smoking status. They were followed at 30 days and 6 months for death, nonfatal myocardial infarction (MI), revascularization procedures, stroke, and need for rehospitalization, and at 1 year for occurrences of death. RESULTS: Overall, 9,971 patients were evaluated, of whom 2,404 (24%) were current smokers, 3,491 (35%) were former smokers, and 4076 (41%) had never smoked. Current smokers were younger (median age 61 years, interquartile range [IQR] 52-67) than former smokers (median age 69 years, IQR 63-75) and never smokers (median age 70 years, IQR 64-77) and had fewer additional coronary artery disease risk factors (hypertension, diabetes, hypercholesterolemia). The 30-day death/MI rate was similar for former versus never smokers (15% vs 13.6%, P = .079) and for current versus never smokers (14% vs 13.6%, P = .585). Adjusted odds ratios for 30-day death/MI in patients receiving enoxaparin compared with those receiving unfractionated heparin were 1.065 (95% CI 0.883-1.283, P = .51) in never smokers, 1.034 (95% CI 0.853-1.254, P = .733) in former smokers, and 0.742 (95% CI 0.582-0.948, P = .017) in current smokers. A significant interaction for treatment and smoking status was found at 30 days (P = .0215), but not at 6 months (P = .1381) or 1 year (P = .1054). One-year unadjusted mortality rates were higher for former versus never smokers (9.1% vs 6.7%, P = .0002) but were similar for current versus never smokers (6.5% vs 6.7%, P = .7226). On follow-up at 30 days, 62.3% (n =1397) of current smokers reported not smoking. CONCLUSIONS: Smokers with non-ST-segment elevation acute coronary syndrome are generally younger and have fewer cardiac risk factors. A significant interaction of smoking and enoxaparin was seen at 30 days, but not sustained at 6 months and 1 year. More than 60% of smokers quit within 30 days of their cardiac event. There was little difference in outcomes from 30 days to 1 year for these smokers who quit versus those who did not.