Nathan.qxp 29/7/08 10:05 Page 18
Acute Coronary Syndromes
Figure 2: Acute Usage of Evidence-based Pharmacotherapies in the
taken. In summary, early invasive management in conjunction with
CRUSADE Registry Demonstrating Underutilization of Anticoagulant
intensive pharmacotherapy remains the preferred approach in
and Antiplatelet Therapies in Otherwise Eligible Patients
intermediate- to high-risk or clinically unstable patients in the absence of
97%
contraindications or patient preference to the contrary.
100
92%
83%
n=29,825
Acute Pharmacotherapies
80
Whereas only a subset of NSTE-ACS patients requires early invasive
60%
cardiac evaluation, virtually all patients benefit from and should ideally
60
%
receive aggressive pharmacotherapies early and indefinitely. Despite the
45%
publication of the aforementioned practice guidelines and the wide
40
availability of related educational initiatives, it remains a significant
challenge for practicing physicians to keep pace with scientific discovery
20
in this area. Acute pharmacotherapies for ACS can be broadly divided
into three classes: anti-ischemic, anticoagulant, and antiplatelet agents.
0
ASA Beta-blockers
Heparin GPIIb/IIIa
Clopidogrel
Anti-ischemic agents such as nitrates offer symptomatic relief of angina,
(UHF + LMWH) inhibitors
while beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, or
Acute medication use within first 24 hours of presentation in the CRUSADE Registry. Data
angiotensin receptor blockers and non-dihydropyridine calcium channel
includes patients enrolled from January 1, 2006 to December 31, 2006 without known
blockers may also yield reductions in ischemic morbidity and mortality in
contraindications to individual medications.
select populations.
1,24
observed between the groups with respect to the primary end-point.
However, the incidence of MI was significantly higher in the early invasive Antiplatelet and anticoagulant therapies, perhaps to a greater extent than
group (15 versus 19%; p=0.005), although rehospitalization was less anti-ischemic therapies, are subject to both controversy and uncertainty.
frequent in the invasive group (7.4 versus 10.9%; p=0.04). Possible These classes of agent have consistently been underutilized in eligible NSTE-
reasons that have been proposed for the lack of benefit of the invasive ACS patients enrolled in the CRUSADE registry, with significant differences
strategy include the trial-specific criteria used to define myocardial noted in rates of use at leading versus lagging institutions (see Figure 2).
25
infarction, the high rate of revascularization in the conservatively Much of the uncertainty stems from the fact that the available data,
managed group (47%), and aggressive medical therapy in both groups. abundant though they may be, have failed to yield one clearly superior
anticoagulant or antiplatelet strategy. Additionally, there are concerns
Despite these conflicting data, several contemporary meta-analyses have regarding bleeding risk and differences between procedural and non-
largely put this issue to rest.
20–22
In these pooled analyses, routine early procedural physicians with respect to choice and timing of various agents.
invasive management was associated with sustained relative reductions However, the fact remains that these agents form the foundation of acute
in ischemic morbidity and mortality and rehospitalization for ischemia of pharmacotherapy for NSTE-ACS and are essential for flow restoration in the
approximately 20–25%. However, a consistent observation is that higher- ‘culprit’ coronary vessel(s) and resolution of intracoronary thrombus both
risk patients benefit more than low-risk patients, in whom neutral or before and after mechanical revascularization.
possibly detrimental effects have been noted. High-risk features that
should direct clinicians to pursue an invasive strategy include findings Anticoagulant Therapy
such as clinical instability or ongoing ischemic symptoms, elevated Indirect antithrombins (unfractionated heparins and LMWHs), direct
cardiac biomarkers (cardiac troponin and/or CK-MB), dynamic thrombin inhibitors (bivalirudin), and factor Xa inhibitors (fondaparinux)
electrocardiogram (ECG) changes, advanced age (>70 years), depressed currently comprise the anticoagulant class. Through binding with
LV systolic function (ejection fraction <40%), prior history of MI, or an antithrombin, unfractionated heparin (UFH) indirectly inactivates
elevated TIMI risk score. While earlier use of invasive therapies in all thrombin (factor IIa) and factors IXa and Xa. Limitations of this
patients selected for this strategy is generally preferred, a recent report compound include non-linear pharmacokinetics, inability to penetrate
from the Can Rapid Risk Stratification of Unstable Angina Patients and resolve organized thrombus, and interaction with plasma proteins
Suppress Adverse Outcomes with Early Implementation of the ACC/AHA and platelets. Nevertheless, the value of UFH has been demonstrated in
Guidelines (CRUSADE) registry found that, although weekend several placebo-controlled trials against the backdrop of aspirin therapy.
presentations of ACS were associated with delays in invasive A meta-analysis of these trials found a 33% relative risk reduction in the
management, there was no increase in in-hospital death or MI, as might short-term incidence of death or MI.
26
Weight-based administration is
be expected.
23
However, it should be noted that in such registry-based strongly preferred to the prior practice of fixed-dose therapy with a
experiences, the role of operator/selection bias cannot be discounted, target activated partial thromboplastin time (aPTT) of 60–80 seconds.
1
and may indeed be the explanation for this seemingly disparate finding.
Importantly, the use of routine or selective invasive therapies does not Low-molecular-weight Heparins
obviate the need to treat all ACS patients with intensive, risk-appropriate LMWHs represent a more homogeneous population of molecules than
medical therapies and risk factor modification. Rather, intensive UFH, and more effectively inactivate factor Xa than thrombin. They also
pharmacological therapies interact in a synergistic fashion with offer more predictable anticoagulant response without the need for
catheterization and coronary intervention, and should therefore be laboratory monitoring. Potential disadvantages of this class include the
implemented even before the invasive management decision has been relative inability to monitor anticoagulant levels, long half-life, and
18 US CARDIOLOGY
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