Pharmacoinvasive Management of Acute Coronary Syndrome: Incorporating the 2007 ACC/AHA Guidelines

High-risk features and treatment trigger criteria for
acute coronary syndromes: Risk-directed therapy and the sliding
scale and hierarchy of care options.
Comparison between ACC/AHA non-ST-elevation
myocardial infarction and ESC non-ST-segment elevation acute
coronary syndrome criteria
Current bleeding definitions according to clinical studies
using antithrombins.
“Major” bleeding in ACS trials and community populations. Bleeding events are more
prevalent than other adverse events, e.g., MI, CHF, and death [Moscucci, 2003; Alexander,
2005; Ferguson, 2004; Cohen, 1997; Peterson, 2004; PURSUIT, 1998; Boersma, 2002;
Figure 2. Excessive dosing of anticoagulants by age.
LMVW = low-molecular-weight; UF = unfractionated; GP IIb/IIIa =
glycoprotein IIb/IIIa inhibitor.
The CATH Clinical Consensus Panel Report - III
The CATH Clinical Consensus Panel Report - III (Cont.)

aMarc Cohen, MD, bJosé Diez, MD, bGlenn N. Levine, MD, cJames J. Ferguson III, MD,
dDavid A. Morrow, MD, MPH, eSunil V. Rao, MD, eJames P. Zidar, MD

Every year, more than 1 million patients are admitted to a hospital with a diagnosis of unstable angina or non-ST-elevation myocardial infarction (UA/NSTEMI).1 Relative to acute ST-elevation myocardial infarction (STEMI), patients with UA/NSTEMI have a slightly higher 1-year mortality rate,2 and constitute a significantly larger proportion of patients with acute coronary syndromes (ACS).3 During the course of their hospitalization, these patients will interact with many different healthcare professionals, be subjected to many different drugs, diagnostic and invasive procedures, and be moved through several different hospital units before being discharged on multiple different medications. While the 2002 American College of Cardiology/American Heart Association Guidelines (ACC/AHA) provided a foundation for management of patients with UA/NSTEMI, a host of recent, prospective, randomized, clinical therapeutic trials of some already-approved antithrombotics as well as newer agents have been published or presented at international meetings involving more than 75,000 patients. In recognition of the fast-moving pace of scientific discovery, the 2002 guidelines were updated and published in late 2007.4 In addition, several recent large clinical trials have presented new options above and beyond those presented in the 2004 American College of Cardiology/American Heart Association Guidelines (ACC/AHA) for the management of patients with STEMI.5
However, despite the new information and updated guidelines, substantial challenges remain in identifying the optimal combination of therapeutic agents that will maximize benefits while minimizing drug-related adverse events in the individual patient with NSTEMI. The decision-making process in terms of choosing among the spectrum of pharmacologic options (e.g., low-molecularweight heparins (LMWHs), unfractionated heparin [UFH], direct antithrombins [DTI], indirect factor-Xa inhibitors, P2Y12 – adenosine diphosphate (ADP) receptor blockers and glycoprotein [GP] IIb/IIIa inhibitors), and the optimal timing for invasive catheterization and percutaneous interventional (PCI) approaches is complicated by the large number of “stakeholders”: emergency physicians, medical cardiologists, interventionalists, cardiac surgeons, nurse practitioners and nurses. Not infrequently, the choices appealing to emergency department providers may be different from the choices interventional cardiologists will make.

The third Cardiac Catheterization and Antithrombotic Therapy in the Hospital (CATH) Clinical Consensus Panel & Scientific Roundtable assembled on November 2, 2007. With the above-mentioned clinical controversies and treatment options as targets, the purpose of the Panel was to critically evaluate recent clinical trial data; elaborate a rational and evidencebased approach to integrating the published and or presented information relating to the direct thrombin inhibitors, indirect and direct anti-Xa agents, and new antiplatelet agents; develop a strategy for invasive care; and outline a site-, specialty- and spectrum-of-care-specific, evidence-based strategy that distinguishes among pharmacological and/or invasive interventions based on risk-group stratification for maximizing outcomes in patients with NSTE-ACS.
The CATH Panel focused on those therapeutic areas in which the most important changes are occurring related to pharmacological management in the setting of PCI: 1) the expanding array of antithrombins such as the LMWH enoxaparin, the indirect, selective Xa inhibitor fondaparinux and the direct selective thrombin inhibitor bivalirudin, including combination with platelet inhibitors: 2) use of aspirin, oral antiplatelet drugs clopidogrel, prasugrel, and/or GP IIb/IIIa inhibitors; 3) identification of high-risk features and treatment trigger points that support either more intensive medical therapy or the need for PCI; and 4) recognition that utilization and choice of agents rests to a large extent on the balance between the benefit of reducing recurrent ischemic events relative to the risks incurred from increasing major and/or minor bleeding events.
Surprisingly, a significant percentage of patients in the United States still do not have immediate access to facilities where cardiac catheterization, PCI and/or coronary artery bypass graft surgery (CABG) services are available. As a result, risk-directed care must also take into account site-specific features as well as the availability of clinical subspecialists. Acknowledging these realities, the CATH Panel (vide infra) has reviewed several recent trials spanning the spectrum from conservative medical therapy to invasive percutaneous therapies, as well as recent trials in STEMI that provide new insights regarding antithrombotic therapy in ACS. The CATH Panel focused on the specific therapeutic issues for each of the three major clinical zones (emergency department, cardiac catheterization laboratory and post catheterization stepdown unit) in which patients with NSTE-ACS are managed.

Because of the broad spectrum of patients presenting with UA/NSTEMI or STEMI ACS, there is no “one-size-fits-all” therapeutic strategy that can be adopted. To assist the clinician in correlating the intensity of the treatment plan with the acuity of the patient, several risk stratification models have been presented in the 2007 ACC/AHA guideline updates. Although the 2002 guidelines recommended an early invasive strategy (diagnostic angiography and revascularization) for UA/NSTEMI, the current guidelines differentiate between high- and low-risk patients with UA/NSTEMI. Risk scores may be used to integrate multiple clinical factors that determine risk. Troponin (Tn) biomarkers of cardiac damage and B-type natriuretic peptide (BNP) markers for assessment of cardiac risk may be useful in risk stratification when integrated into an overall clinical risk score. Perhaps one of the most important aspects of managing patients with NSTE-ACS is the ability to risk-stratify patients into those individuals who will benefit most from either pharmacological or an early invasive strategy. Although a number of risk stratification tools have been suggested by clinical experts and associations, the Thrombolysis in Myocardial Infarction (TIMI) Risk Score has emerged as one of the most widely accepted approaches to date for identifying patients who are most likely to benefit from specific strategies.6 The TIMI Risk Score is derived from the sum of the following clinical parameters, each assigned a value of one point: 1) diagnostic elevation of cardiac markers; 2) history of 3 or more conventional cardiac risk factors (e.g., diabetes, smoking, elevated low-density lipoprotein cholesterol, hypertension or family history of premature coronary artery disease [CAD]); 3) age ≥ 65 years; 4) known CAD, defined as documented ≥ 50% stenosis in at least 1 major coronary artery; 5) aspirin use within 1 week of presentation; 6) 2 or more episodes of resting angina during the previous 24 hours prior to presentation; and 7) new STsegment deviation (persistent depression or transient elevation not meeting fibrinolytic criteria) of ³ 0.5 mm in limb and/or precordial leads.6 As the number of risk factors increases from 0–1 to 5–7, the risk of death, MI, or urgent revascularization within 14 days increases from 4.7% to 40.9% in a stepwise fashion.
More recently, additional makers providing prognostic information in patients with ACS, such as C-reactive protein (CRP), BNP and renal dysfunction, have been identified in addition to cardiac Tn.7,8 In patients with ACS, BNP and Nterminal prohormone brain natriuretic peptide (NT-proBNP) are prognostic for mortality and new heart failure, but are less consistently so for recurrent MI.9 However, until specific therapeutic recommendations can be made, the routine use of BNP and NT-proBNP in all patients with suspected ACS cannot be recommended.
BNP has been added to the guidelines as a biomarker test that can be considered to supplement global risk assessment in ACS patients based upon consistent data from more than 10 clinical studies.

High-risk criteria that support more aggressive medical therapy (i.e., addition of a small-molecule GP IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin or other anticoagulant, and clopidogrel), or that direct clinicians toward early catheterization and revascularization as the dominant modality for patients with ACS are outlined in Table 1. Additional factors to consider include the presence of such comorbid conditions as heart failure, prior MI, previous CABG and left ventricular (LV) dysfunction. Patients with advanced renal disease, clearly a group at higher risk for recurrent ischemic events, must be approached cautiously given the risks of contrast-induced nephropathy and bleeding. When serum creatine levels are > 4.0 mg/dL, alternative strategies may need to be considered.

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