Nathan.qxp 5/8/08 11:07 Page 19
Non-ST-segment Elevation Acute Coronary Syndromes
incomplete reversal with protamine sulfate. Dalteparin, nadroparin, and fondaparinux over enoxaparin at 30 and 180 days was largely driven by
enoxaparin have all been studied against UFH in NSTE-ACS. While decreased major bleeding. Further evidence of the more modest
dalteparin and nadroparin appear comparable to UFH in terms of anticoagulant effect of fondaparinux was the excess of catheter
reduction in death and MI, enoxaparin has demonstrated reductions in thrombosis seen in fondaparinux-treated patients undergoing coronary
death and MI compared with UFH. In a meta-analysis of six randomized angiography, necessitating additional peri-procedural dosing with UFH.
controlled trials of enoxaparin versus UFH, a 9% relative risk reduction in Thus, fondaparinux is also an anticoagulant option for NSTE-ACS
30-day death and MI was seen with enoxaparin, with no significant management, albeit a less attractive choice in patients undergoing early
differences in major bleeding or transfusion.
27
Concerns regarding invasive evaluation.
33,34
excessive bleeding with enoxaparin were raised by the Superior Yield of
the New Strategy of Enoxaparin, Revascularization and Glycoprotein Antiplatelet Therapy
IIb/IIIa Inhibitors (SYNERGY) trial, and may be linked in part to Activated platelets play a central role in the initiation and propagation of
administration of pre-randomization anticoagulant therapies with ‘cross- vascular thrombosis. Circulating quiescent platelets adhere to the site
over’ to enoxaparin.
28
Additional insights into the bleeding hazard were of vascular injury, triggering a variety of intracellular signaling
gained by a CRUSADE registry analysis, which found that anticoagulants mechanisms that further strengthen the adhesive process and result in
and antiplatelet agents were frequently overdosed, with a resultant
increase in bleeding and transfusion.
29
Until these issues are clarified, it is
generally recommended that consistent anticoagulant therapy be
Despite the significant advances that have
maintained throughout the treatment course with due deference to
been made in diagnostic technologies, the
weight-, age-, and renal-clearance-related dosing considerations.
availability of newer therapeutic agents,
Direct Thrombin Inhibitors
and greater access to invasive therapies,
Direct thrombin inhibitors (DTIs) block thrombin via direct binding to the
molecule at three possible sites: the active catalytic site and exosites 1
many challenges remain in the
and 2. DTIs offer several potential advantages over indirect thrombin
management of non-ST-segment elevation
inhibitors, as antithrombin is not required as a co-factor, both circulating
and clot-bound thrombin are inhibited by DTIs, and there is no activation
acute coronary syndromes
of platelets. The bivalent DTIs hirudin and bivalirudin (a bio-engineered
form of hirudin) bind thrombin at the active site and exosite 1. The latter platelet activation. Numerous endogenous agonists have been implicated
agent is particularly attractive for use in ACS management and PCI as it in the platelet activation sequence, with thrombin, adenosine
undergoes cleavage by bound thrombin, with return of active-site diphosphate (ADP), epinephrine, and thromboxane A2 (TXA2) playing
function and a resultant short biological half-life.
30
Use of bivalirudin prominent roles. Upon activation, various soluble adhesive proteins,
monotherapy in invasively managed intermediate- to high-risk NSTE-ACS growth factors, platelet agonists, and pro-coagulant substances are
patients was evaluated in the Acute Catheterization and Urgent either expressed on the platelet surface or released into circulation from
Intervention Triage Strategy (ACUITY) trial.
31,32
When viewed from the cytoplasmic granules. Importantly, the GPIIb/IIIa (aIIb/b3 integrin)
perspective of net clinical benefit (inclusive of cardiovascular morbidity, receptor found abundantly on the surface of the quiescent platelet
mortality, and protocol-specified bleeding end-points), the use of undergoes conformational activation and further upregulation.
35
The
bivalirudin with provisional use of GPIIb/IIIa inhibitors was non-inferior to observed complexity of the activation sequence serves as the rationale
a strategy of heparin and mandatory GPIIb/IIIa inhibition. A modest for the use of multiple complementary antiplatelet agents in the
increase in ischemic events with bivalirudin monotherapy was management of coronary thrombosis. Three classes of agent play a major
counterbalanced by decreases in major and minor bleeding. While this role in the management of NSTE-ACS: aspirin, thienopyridines, and
data set in many ways mirrored contemporary, registry-derived patterns platelet GPIIb/IIIa receptor inhibitors. Aspirin inhibits platelet aggregation
of resource utilization in ACS, several important caveats should through irreversible inhibition of platelet cyclo-oxygenase-1-mediated
be acknowledged when applying these data to clinical practice. generation of thromboxane A2. Pooled data from 195 trials including
Pre-catheterization use of clopidogrel enhanced the efficacy of the 143,000 patients have demonstrated a 22% risk reduction in the odds of
bivalirudin strategy to a greater degree than in the GP inhibitor groups. MI, stroke, or vascular death with aspirin versus placebo when used in
Very early cardiac catheterization limited the duration of post- the capacity of secondary prevention.
36
In suspected or definite ACS,
randomization protocol-assigned therapies prior to PCI. Therefore, in aspirin should be administered immediately (162–325mg) and continued
high-risk patients, those manifesting recurrent ischemic symptoms, or indefinitely in the absence of contraindications or adverse reactions.
when a delay to angiography is anticipated, the use of clopidogrel and/or
GPIIb/IIIa inhibition in conjunction with consistent anticoagulant therapy Oral Platelet Antagonists
may be more effective than DTI monotherapy. Fondaparinux is a synthetic Thienopyridines (ticlopidine, clopidogrel) exert their antiplatelet effect by
pentasaccharide that avidly binds antithrombin and rapidly inhibits factor permanently binding with the ADP P2Y12 platelet surface receptor,
Xa. This compound was tested in NSTE-ACS patients against enoxaparin which in turn downregulates activity of the GPIIb/IIIa receptor complex.
in the Organisation to Assess Strategies in Acute Ischaemic Syndromes Clopidogrel in conjunction with aspirin was shown in the Clopidogrel in
(OASIS)-5 trial and was non-inferior with respect to death, MI, or Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial to
refractory ischemia at nine days. Interestingly, the mortality benefit of reduce major adverse early and late cardiac events following admission
US CARDIOLOGY 19
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