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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3947_Библиотеки_им_академика_М_И_Перельмана
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Synthetic Factor Xa Inhibition in Acute Coronary Syndromes
the fondaparinux arm (0.9% vs. 0.4%). The occurrence of catheter-related thrombus was associated with
a very high rate of MI and stroke (27% and 5.4%, respectively) underscoring the significant morbidity
of such an event. An amendment to the OASIS-5 protocol was made following an interim analysis of
these events allowing the use of open label UFH at the discretion of the investigator. In the remainder of
the study, nine of the ten events of catheter-related thrombus in the fondaparinux arm occurred in
patients who did not receive adjunctive UFH. Despite the fact that overall outcomes in the PCI subset
with fondaparinux were reassuring in this study, interventional cardiologists will likely be concerned by
the potential for an uncommon but serious event such as guide catheter thrombosis. This may hamper
the widespread application of fondaparinux in patients with ACS. The ability to provide a point-of-care
assay to assess the anticoagulant effect of selective Xa inhibitors, and to correlate this measurement with
clinical outcomes might be a first step in addressing this important issue. In addition, the efficacy and
safety of the strategy of upstream fondaparinux with the use of standard UFH at the time of PCI as
recommended by the study authors needs to be tested in prospective clinical studies.
In summary, OASIS-5 demonstrated that low-dose fondaparinux was equivalent to enoxaparin in
its short-term efficacy in preventing ischemic events among high-risk patients with UA or NSTEMI
and resulted in a substantial reduction in major bleeding, a finding that was associated with a reduction
in long-term morbidity and mortality. Although there was an overall net clinical benefit in the PCI
cohort, the issue of guide catheter thrombosis needs to be addressed and effective strategies for its
prevention in patients receiving fondaparinux therapy are required.
Fig. 6. Drug dosing in the PCI cohort of OASIS-5. (a) Fondaparinux arm; (b) Enoxaparin arm. GP IIb/IIIa
Glycoprotein IIb/IIIa inhibitor; UFH Unfractionated heparin.
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OASIS-6 – STEMI
The Sixth Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS-6) trial
was a randomized, double-blinded trial comparing fondaparinux to “usual care” in 12,092 patients
with
STEMI (37). The trial design was complex in that patients were allocated to two separate strata
based on the need for antithrombotic therapy, as determined by the enrolling physician (Fig.
7). The
first stratum included patients lacking a strict indication for antithrombotic therapy. Patients in this
stratum were randomized to fondaparinux or placebo. The second stratum included patients in whom
antithrombotic therapy was indicated, such as those who received fibin-specific lytic therapy, were
undergoing PCI, or were managed conservatively with no reperfusion therapy. All patients in this
stratum were randomized to fondaparinux or UFH. Patients in stratum 2 who underwent PCI were
prerandomized to one of four possible drug regimens (UFH alone, GpIIb/IIIa inhibitor alone, UFH
and Gp IIb/IIIa inhibitor, or neither medication).
Subsequent dosing of the randomized agent (i.e.,
fondaparinux or UFH) was based on the prerandomized regimen.
The study’s primary endpoint was death or recurrent MI at 30 days. Secondary outcomes included
evaluation of these same clinical endpoints at 9 days and at study’s end (3–6 months). The primary
safety outcome was the incidence of bleeding complications at 9 days.
In the pooled analysis of patients from both strata, treatment with fondaparinux resulted in a
significant reduction in the composite endpoint of death or MI at 9 and 30 days (primary endpoint),
and at 3–6 months (Table 2). Somewhat surprisingly, treatment with fondaparinux resulted in a
significant reduction in overall mortality at all three time points. In terms of bleeding complications,
there was a trend toward fewer severe and major bleeding episodes with fondaparinux at 9 days.
Overall, the results were consistent for patients in stratum 1 and 2.
The sub-analysis of outcomes in patients from stratum 2, however, revealed some important findings
that suggested a distinct dichotomy of clinical response to fondaparinux based on the performance of
primary PCI. At study end, patients who received fondaparinux and did not undergo primary PCI had
a significantly lower incidence of death or reinfarction (14.9% vs. 19%, P
= 0.008) and demonstrated a
trend toward less major bleeding events at 9 days (Fig.
8). In contrast, patients who received fondaparinux
Fig. 7. Treatment algorithm for patients in OASIS-6.
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Synthetic Factor Xa Inhibition in Acute Coronary Syndromes
Table 2
Clinical outcomes in OASIS-6
Time (days) Clinical endpoint Fondaparinux (%) Placebo or UFH (%)
9 Death or reinfarction 7.4 8.9
Severe bleeding 1.0 1.3
Major bleeding 1.8 2.1
Death 6.1 7.0
30 Death or reinfarction 9.7 11.2
Death 7.8 8.9
Study end Death or reinfarction 13.4 14.8
Death 10.5 11.6
Fig. 8. Clinical and safety outcomes in patients not undergoing PCI in OASIS-6. (a) Incidence of death or recurrent
myocardial infarction (MI); (b) Incidence of bleeding.
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Antithrombotic Drug Therapy in Cardiovascular Disease
and underwent PCI, derived no mortality benefit at 3–6 months (6.1% vs. 5.9%), and had a trend
toward an increased incidence of major bleeding episodes at 9 days (Fig. 9). The explanation for this
dichotomy is not entirely clear. Patients undergoing PCI in stratum 2 were at lower predicted risk and
received a shorter duration of antithrombotic therapy compared to patients who received thrombolytic
therapy or no reperfusion therapy. In addition, the specter of guide catheter thrombosis was again
observed in the fondaparinux arm of this trial, with 22 events in patients treated with fondaparinux and
no events in the UFH arm. The adverse consequence(s) of guide catheter thrombosis may have contrib-
uted to the overall lack of benefit observed in the PCI cohort. These data underscore how rare catheter
thrombosis occurs in patients receiving standard treatment with UFH, and will certainly create reluc-
tance on the part of interventional cardiologists to abandon the gold standard of anticoagulation in favor
of more novel anticoagulants which have not proven the same degree of procedural safety. In a post
hoc analysis, the investigators did report that among patients who were randomized to the fondaparinux
arm and who received adjunctive UFH at the time of PCI, clinical event rates were similar to controls.
This suggests that the addition of UFH at the time of PCI in patients who have received upstream fon-
Fig. 9. Clinical and safety outcomes of patients undergoing PCI in OASIS-6. (a) Incidence of death or recurrent
myocardial infarction (MI); (b) Incidence of bleeding.
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Synthetic Factor Xa Inhibition in Acute Coronary Syndromes
daparinux for the treatment of STEMI may largely prevent adverse complications and may ultimately
prove to be the best treatment strategy for this subset of patients.
ACC UA/NSTEMI GUIDELINES – UPDATE 2007
The use of fondaparinux is now specifically addressed in the most recent American College of
Cardiology/American Heart Association (ACC/AHA) guidelines for the management of an unstable
angina and N
STEMI (38).
Fondaparinux receives a Class I indication for use in patients with UA/N
STEMI in whom a
conservative strategy is selected. Furthermore, fondaparinux is recommended as the anticoagulant
agent of choice in patients who have an increased risk of bleeding and in whom a noninvasive strategy
is selected. In all cases, treatment with fondaparinux should be initiated at a subcutaneous dose of
2.5
mg administered daily once a conservative strategy has been planned and continued for the duration
of hospitalization or up to 8 days. Given the concern of guide catheter thrombosis raised in the
OASIS-5 and OASIS-6 trials, the task force also recommends the administration of adjunctive UFH
(50–60
units/kg) at the time of PCI in patients who receive upstream fondaparinux.
COST-ANALYSIS OF FONDAPARINUX IN ACS
Economic data on the use of fondaparinux are limited to its use in the prevention and treatment of
venous thromboembolism where it has clearly demonstrated overall cost-efficacy
(39,40). Although
health economic studies on the use of fondaparinux in AC
S have yet to be carried out, interpolation of
existing data suggests that fondaparinux usage may result in an overall health care cost savings for several
reasons, including lower and uncomplicated administration doses and decreased rates of bleeding when
compared to traditional antithrombotic therapies in specific patient subsets. Further studies formally
investigating the cost-effectiveness of this novel antithrombotic agent, however, are required.
CONCLUSION
Fondaparinux is a unique antithrombotic agent that selectively inhibits factor Xa. Until recently,
the role of fondaparinux in AC
S remained undefined. The OASIS-5 and OASIS-6 trials, however,
have demonstrated the overall safety and efficacy of fondaparinux in the treatment of patients presenting
with UA, N
STEMI, and STEMI. The major challenge for the more widespread application of this
agent in these clinical settings is the management of the subset of ACS patients who ultimately require
PCI. Prospective randomized studies documenting the efficacy and safety of using adjunctive UFH at
the time of PCI in patients receiving fondaparinux would aid significantly in this regard.
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Part IV
Antithrombotic Therapy for STEMI
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11 Antiplatelet Therapies: Aspirin, Clopidogrel
and Thienopyridines, and Glycoprotein
IIb/IIIa Inhibitors for the Management of
ST-Segment Elevation Myocardial Infarction
Rory B. Weiner and Marc S. Sabatine
Co n t e n t s
Background
Aspirin
Thienopyridines
Glycoprotein (Gp) Iib/Iiia Receptor Inhibitors
Future Directions
References
Ab s t r A c t Platelet adhesion, aggregation, and activation play a key role in initiating and propagating coronary
thrombosis. This provides opportunities to pharmacologically interfere with platelet function and antiplatelet
therapies are a central component in the treatment of acute coronary syndromes. Whether the reperfusion strat-
egy for ST-segment elevation myocardial infarction (STEMI) is pharmacologic or catheter-based, the use of
adjunctive antiplatelet therapy can reduce the rate of death and ischemic complications. Aspirin, an irreversible
inhibitor of platelet cyclooxygenase 1, provides mortality benefit to STEMI patients and is a cornerstone of
therapy. Thienopyridines inhibit platelet activation and aggregation by targeting the P2Y
12
adenosine diphos-
phate (ADP) receptor and have been shown to provide mortality benefit in STEMI patients. Clopidogrel is pre-
ferred over ticlopidine due to a more favorable side effect profile. The Clopidogrel as Adjunctive Reperfusion
Therapy – Thrombolysis in Myocardial Infarction 28 trial (CLARITY – TIMI 28) and the Clopidogrel and
Metoprolol Infarction Trial/the Second Chinese Cardiac Study (COMMIT/CCS – 2) are two recent landmark
trials demonstrating mortality benefit with clopidogrel in patients receiving pharmacologic reperfusion for
STEMI. The glycoprotein (GP) IIb/IIIa receptor mediates platelet aggregation induced by all physiologic
agonists and blockade of the receptor, either by monoclonal antibodies (abciximab) or by small molecules
(eptifibatide and tirofiban), can be used in adjunctive treatment of STEMI, particularly in patients receiving
primary percutaneous intervention (PCI). Novel antiplatelet agents, which may address issues relating to vari-
ability in response and irreversibility of inhibitor effects, are under active investigation and will better refine the
role of antiplatelet therapy in this clinical setting and lead to further improvement in patient outcomes.
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_11
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
Key words: Platelet; ST-segment elevation myocardial infarction (STEMI); Aspirin; Clopidogrel;
Glycoprotein (GP) IIb/IIIa inhibitor
BACKGROUND
Platelet adhesion, aggregation, and activation play a key role in initiating and propagating coronary
thrombosis. In response to vascular injury, platelets interact with components of the subendothelial
matrix, notably collagen and von Willebrand factor
(1). Various local mediators, such as adenosine
diphosphate (ADP), thromboxane A
2
(TXA
2
), and thrombin are then produced and amplify platelet
activation
(2). This sequence provides multiple opportunities to pharmacologically interfere with
platelet activation, and antiplatelet therapies are a central component in the treatment of all acute coronary
syndromes (ACS).
Whether the reperfusion strategy employed for ST-segment elevation myocardial infarction (STEMI)
is pharmacologic or catheter-based, the use of adjunctive antiplatelet therapy is crucial to reduce the rate
of death and ischemic complications. The focus of this chapter will be antiplatelet therapies, including
aspirin, thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors, in the management of STEMI.
ASPIRIN
Aspirin irreversibly inhibits platelet cyclooxygenase 1 (COX-1) through acetylation of the amino acid
serine at position 529, thereby preventing the formation of prostaglandin H
2
from the precursor arachidonic
acid. This blocks the subsequent formation of TXA
2
, a potent mediator of platelet aggregation (3).
In 1988, the use of aspirin in the ISIS-2 (Second International Study of Infarct Survival) trial
conferred a 23% reduction in vascular mortality compared with placebo alone in patients with STEMI (4).
In this trial, over 17,000 patients were randomized to SK versus placebo and aspirin versus placebo in
a 2 × 2 factorial design. The mortality benefit for aspirin was similar to the 25% reduction in death
with SK alone. Furthermore, the combination of aspirin and SK provided additive benefit, with a 42%
reduction in mortality rate (8.0% for the combination vs. 13.2% for placebo; p
< 0.001; Fig. 1).
It has been hypothesized that fibrinolysis may in itself promote platelet aggregation, possibly by
exposure of the clot’s platelet-rich core or through the release of thrombin. A meta-analysis demon-
strated that aspirin reduced coronary reocclusion and recurrent ischemic events after fibrinolytic
therapy with either streptokinase or alteplase (5). Long-term follow-up data have demonstrated that
the early survival advantage of SK and aspirin therapy is maintained over 10 years
(6).
Fig. 1. Incidence of vascular death for patients in the ISIS-2 trial randomized to treatment with placebo, aspirin, or a
combination of streptokinase and aspirin after 5 weeks’ follow-up.
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