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304 PART 3: Cardiovascular Disorders

■ ANTICOAGULANT THERAPY composite ischemia, and reduced major bleeding, but patients who got

Heparin is an important component of primary therapy for patients bivalirudin alone without a thienopyridine prior to angiography or PCI
had a higher rate of ischemic events. Bilvalirudin should not be admin-
with unstable coronary syndromes without ST elevation. When added
to aspirin, heparin has been shown to reduce refractory angina and istered alone, particularly if there is a going to be a delay to angiography.
the development of myocardial infarction, and a meta-analysis of the Glycoprotein IIb/IIIa Antagonists: The benefits of glycoprotein IIb/IIIa
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available data indicates that addition of heparin reduces the composite inhibitors as adjunctive treatment in patients with acute coronary
end point of death or MI. 114 syndromes have been shown in several trials. 120-122 Meta-analyses
Heparin, however, can be difficult to administer, because the antico- have found a relative risk reduction of 11% in NSTEMI. Additional
71
agulant effect is unpredictable in individual patients; this is due to heparin analysis suggests that glycoprotein IIb/IIIa inhibition is most effec-
binding to heparin-binding proteins, endothelial and other cells, and hep- tive in high-risk patients, those with either ECG changes or elevated
arin inhibition by several factors released by activated platelets. Therefore, troponin. The benefits appear to be restricted to patients undergo-
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the APTT (activated partial thromboplastin time) must be monitored ing percutaneous intervention, which may not be entirely surprising.
closely. The potential for heparin-associated thrombocytopenia is also a These studies were conducted prior to the era of dual antiplatelet
safety concern. therapy. As mentioned previously, it is common practice to administer
Low molecular weight heparins (LMWH), which are obtained by a thienopyridine and aspirin in conjunction with an anticoagulant in
depolymerization of standard heparin and selection of fractions with patients with ACS. For patients with UA/NSTEMI undergoing an initial
lower molecular weight, have several advantages. Because they bind less invasive approach, the most recent data suggest that either a glycoprotein
avidly to heparin binding proteins, there is less variability in the antico- IIb/IIIa inhibitor or a thienopyridine can be given in addition to aspirin
agulant response and a more predictable dose-response curve, obviating and an anticoagulant if the patient is considered low-risk (troponin neg-
the need to monitor APTT. The incidence of thrombocytopenia is lower ative). However, if the patient is considered high-risk (troponin positive,
(but not absent, and patients with heparin-induced thrombocytopenia recurrent ischemic features) both a glycoprotein IIb/IIIa inhibitor and
with antiheparin antibodies cannot be switched to LMWH). Finally, clopidogrel can be given in addition to aspirin and an anticoagulant. 41,112
LMWHs have longer half-lives, and can be given by subcutaneous
injection. These properties make treatment with LMWH at home after ■ INTERVENTIONAL MANAGEMENT
hospital discharge feasible. Since evidence suggests that patients with
unstable coronary syndromes may remain in a hypercoagulable state for Cardiac catheterization may be undertaken in patients presenting with
weeks or months, the longer duration of anticoagulation possible with symptoms suggestive of unstable coronary syndromes for one of several
LMWH may be desirable. reasons: to assist with risk stratification, as a prelude to revasculariza-
Several trials have documented beneficial effects of LMWH therapy tion, and to exclude significant epicardial coronary stenosis as a cause of
in unstable coronary syndromes. The ESSENCE trial showed that the symptoms when the diagnosis is uncertain.
LMWH enoxaparin reduced the combined end point of death, MI, or An early invasive approach has now been compared to a conserva-
115
recurrent ischemia at both 14 and 30 days when compared to heparin. tive approach in several prospective studies. Two earlier trials, the
123
45
Similar results were found in the TIMI 11B trial comparing enoxa- VANQWISH trial and the TIMI IIIb study were negative, but the
116
parin to heparin. A meta-analysis of these two very similar trials difference in the number of patients who had been revascularized by
demonstrated a 23% 7-day and an 18% 42-day reduction in the harder the end of these trials was small. In addition, these trials were performed
117
end point of death or MI. Dalteparin, another low molecular weight before widespread use of coronary stenting and platelet glycoprotein
heparin, is also available, but the evidence for its efficacy is not nearly as IIb/IIIa inhibitors, both of which have now been shown to improve
compelling as that for enoxaparin. 118 outcomes after angioplasty.
Although LMWHs are substantially easier to administer than stan- The FRISC II, TACTICS-TIMI 18, and RITA III trials each demon-
dard heparin, and long-term administration can be contemplated, they strated that the composite end point of death, MI, or refractory angina
are also more expensive. Specific considerations with the use of LMWH was less frequent among patients who were randomized to the early
include decreased clearance in renal insufficiency and the lack of a invasive strategy, with the greatest benefit observed in high-risk patients:
commercially available test to measure the anticoagulant effect. LMWH those with elevated cardiac biomarkers, extensive ST segment depres-
118,124,125
should be given strong consideration in high-risk patients, but whether sion, and hemodynamic features suggestive of large infarctions.
substitution of LMWH for heparin in all patients is cost-effective The ICTUS trial enrolled 1200 patients with UA/NSTEMI who
is uncertain. were initially treated with aspirin and enoxaparin before randomized
assignment to one of two strategies: an early invasive strategy within 48
Direct Thrombin Inhibitors: Recombinant hirudin, argatroban, and hours that included abciximab for PCI or a selective invasive strategy.
126
bivalirudin are examples of direct thrombin inhibitors (DTIs). Unlike Patients who were assigned the latter strategy were selected for coronary
heparin, they directly bind to both circulating and clot bound throm- angiography only if they had refractory angina despite medical treat-
bin and inhibit the conversion of fibrinogen to fibrin in the final step ment, hemodynamic or rhythm instability, or predischarge exercise
of the clotting cascade. Direct thrombin inhibitors have several theo- testing demonstrated clinically significant ischemia. The trial showed no
retical advantages over heparin, including lack of binding to plasma reduction in the composite end points of death, nonfatal MI, or rehos-
proteins, and lack of binding to platelet factor 4, which avoids the pitalization for angina at one year among patients who were assigned
problem of heparin-induced thrombocytopenia. to the early invasive strategy. After four years of follow-up, the rates of
Bivalirudin is the only DTI indicated for use in ACS. The REPLACE death and MI among the two groups of patients remained similar. It is
126
2 trial compared bivalirudin plus provisional glycoprotein IIb/IIIa inhibi- not clear why the results of ICTUS differ from previous trials. The more
tor to unfractionated heparin plus planned glycoprotein IIb/IIIa inhibitor recent Timing of Intervention in Acute Coronary Syndromes (TIMACS)
in 6010 patients undergoing planned or urgent PCI, and although study randomized 3031 patients with UA/NSTEMI to undergo cardiac
6-month event rates with bivalirudin were slightly higher, bleeding was catheterization either within 24 hours of symptom onset or more than
127
lower and the prespecified composite end point met statistical criteria 36 hours later. The median time to angiography was 14 hours for
for noninferiority. Similar findings were seen in the ACUITY trial, the early intervention group and 50 hours for the delayed-intervention
119
which compared heparin with glycoprotein IIb/IIIa inhibition to bivali- group. There was no difference between the groups in the composite end
rudin with glycoprotein IIb/IIIa inhibition to bivalirudin alone with pro- point of death, myocardial infarction, or stroke at 6 months.
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visional glycoprotein IIb/IIIa inhibition. Bivalirudin alone compared Risk stratification is the key to managing patients with NSTEMI acute
with heparin plus GP IIb/IIIa inhibitors resulted in noninferior rates of coronary syndromes. One possible algorithm for managing patients

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