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| Dr Pierre Aubry is a Consultant
Cardiologist at the Bichat-Claude
Bernard Hospital in Paris. He trained
at Paris VII University and became a
certified Cardiologist in 1983. He
has a particular interest in
interventional cardiology. He has
been involved in clinical studies
focusing on antithrombotic therapy,
contrast media, stent devices, and
management of acute coronary
syndromes. His current research
interests include prevention of
contrast-induced nephrotoxicity,
evaluation of efficiency of
antiplatelet agents and thrombin
inhibitors, and percutaneous closure
of atrial septal defects. Dr Aubry has
published in peer-reviewed journals
including the New England Journal
of Medicine, Circulation, and the
Journal of the American College of
Cardiology, and he is a reviewer for
Catheterization and
Cardiovascular Interventions. |
Review of antithrombotic therapy for percutaneous coronary interventions
Pierre Aubry,MD, Mohamed
Majdoub,MD, Antoine Sauguet, MD
Department of Cardiology
Groupe Hospitalier Bichat-Claude Bernard, Assistance
Publique-Hôpitaux de Paris, Paris, France.
Address for correspondence:
Dr Pierre Aubry
Département de Cardiologie,
Groupe Hospitalier Bichat-Claude Bernard,
46 rue Henri Huchard, 75018 Paris, France.
Tel : +33-1-40-25-86-65
Fax : +33-1-40-25-88-65
Email: pcaubry@yahoo.fr
Abstract
Antithrombotic therapy is a cornerstone in the
management of acute coronary syndromes and plays a
major role during percutaneous coronary interventions.
Numerous antithrombotic agents are currently
available, showing synergistic effects in combination. In
considering the physiological basis of thrombosis,
platelets and coagulation are seen as interdependent
and cannot be dissociated in therapeutic strategies.
Nevertheless, new antithrombotic agents and new
protocols are emerging.
The use of potent antithrombotic agents may be
associated with increased bleeding complications and
additional costs.With this in mind, recommendations
and expert consensus documents aim to help
interventionists in clinical practice. Currently, dual
antiplatelet therapy with aspirin and clopidogrel is the
standard treatment after stenting, although
development of direct thrombin inhibitors may soon
change anticoagulation practices. Indications for
intravenous GP IIb-IIIa antagonists need to be redefined
according to current management of acute coronary
syndromes and reliable tests are needed for the
monitoring of antiplatelet activity. Insufficient platelet
inhibition with standard therapy should be discussed
when subacute stent thrombosis occurs. In addition to
technological advances with newer devices, further
studies must continue to assess antithrombotic
strategies in terms of protective effects and bleeding risks.
Introduction
 |
Percutaneous coronary intervention (PCI) with stent
implantation needs appropriate antithrombotic therapy.
Thrombosis may influence outcome after PCI, a procedure that produces vessel injury and induces
thrombin generation and platelet activation with
intertwined pathways. Numerous antithrombotic agents
are currently available (Tables 1 and 2).
Guidelines and expert consensus documents aim to help
interventionists to weigh up the benefits and risks of
procedures.1,2 Newer antithrombotic agents are
emerging as an alternative to conventional treatments;
however, data supporting their use are still limited.
Recommendations issued by different organizations are
not homogeneous and do not cover all subjects. In
addition, burdens and costs of treatments may
influence the operator’s choices. Finally, individual
variability of response to antiplatelet therapy is a
recurrent question. This paper summarizes recent
recommendations of antithrombotic therapy for PCI
and discusses some debated points.
 |
Trends in the evolution of antithrombotic
therapy for PCI
With the progressive introduction of stents, the need
for less aggressive anticoagulation has emerged.3
Increased use of stents, as well as decreased use of
anticoagulation, has been associated with reduced rates
of ischaemic and bleeding complications. More recently,
a clear benefit of early revascularisation and aggressive
antiplatelet therapy has been demonstrated for highrisk
patients who should be identified. Risk markers of
NSTE-ACS (non-ST-elevation acute coronary
syndromes) recognised in ESC guidelines4 are listed
in Table 3.
Recommendations
Strong clinical recommendations (i.e. evidence
that a treatment is beneficial with data derived
from multiple randomized clinical trials) are few
in number. Recent ESC recommendations on
antithrombotic therapy during PCI are summarized
in Table 4 and show some differences from the ACCP
recommendations.1,2 Experts recommend against
intra-coronary fibrinolytic agents during PCI,
ticlopidine beyond 14 days after stenting, and
prolonged heparin infusion after PCI.
 |
Aspirin
Studies showing a significant reduction of major
vascular events with aspirin were generally performed
before the widespread use of PCI. These results have
been extrapolated to PCI for which aspirin is considered
as the cornerstone of antiplatelet therapy. A daily dose in the range of 75–100 mg is sufficient in association
with a thienopyridine,5 while higher doses are
associated with increase in bleeding complications
without supplementary protective effect.
Thienopyridines
By acting on different platelet proteins (COX-1, ADP
receptor P2Y12), aspirin and thienopyridines have
synergistic effects for platelet inhibition.5 This dual
antiplatelet therapy has become the standard of care
following stent placement.6,7 Clopidogrel seems to be at least as effective as ticlopidine with fewer side-effects.8
Consequently, ticlopidine is no longer used in
most countries.
Anticoagulation during PCI
PCI without anticoagulation appears unrealistic.
However, there are few controlled trials specifically
addressing the use of heparin during PCI. The optimal
dose of unfractionated heparin (UFH), the most
commonly used anticoagulant during PCI, remains
unknown9 – weight-adjusted low doses appear at least as safe as fixed high doses.10 At the start of PCI, a
50–100 UI/kg bolus of UFH is now recommended. If GP
IIb-IIIa inhibitors are given, use of low doses of UFH
(50–70 UI/kg) limits bleeding complications.11 During
PCI, the objectives of anticoagulation may differ:
treatment of ACS and prevention in clot formation on
materials do not necessarily require a similar inhibition
of coagulation factors IIa and Xa.
Unfractionated heparin versus low-molecular-weight
heparins (LMWH)
Use of the same anticoagulant agent seems judicious
for NSTE-ACS undergoing PCI. The superiority of LMWH
over UFH is clear for ACS.12 The most recent guidelines
do not suggest that LMWH may supplant UFH in PCI.1,2
Registries generally reported a trend towards increased
bleeding complications with LMWH in comparison with
UFH.13 If PCI is performed within 8 hours of the last
subcutaneous injection of LMWH, no further
anticoagulation is needed.14 Yet, despite its limitations,
UFH remains the standard heparin therapy during PCI.
Monitoring of anticoagulation activity
The activated clotting time (ACT) is easily measured in
the cath lab and gives a global assessment of the level
of anticoagulation for UFH and bivalirudin.With UFH
regimen, target ACT values in the range of 250–350 s
or 200–250 s (if GP IIb-IIIa antagonists are given), are
advocated during PCI.1 The monitoring of UFH activity
by ACT is not systematic if weight-adjusted doses are
used. The fact that subcutaneous LMWH slightly
modifies the ACT is an issue for the monitoring of
anticoagulation activity.9 On the other hand, ACT may
measure anticoagulation activity of LMWH following
intravenous administration.15
Use of intravenous GP IIb-IIIa inhibitors
Based on the results of controlled trials, upstream use
of GP IIb-IIIa inhibitors is recommended prior to PCI in
moderate-to-high-risk patients with NSTE-ACS.4,5
Currently, these agents are often started in the cath lab once the coronary anatomy is known and PCI is
planned. The burdens and costs of these agents may
explain this practice and a multinational registry showed
a relatively infrequent use of GP IIb-IIIa inhibitors in the
real world.16 Recommendations for GP IIb-IIIa inhibitors
are often derived from non PCI-trials and the position of
these agents needs to be redefined using contemporary
studies (i.e. planned PCI with stenting in all patients).
New direct thrombin inhibitors
Thrombin, a key modulator of haemostasis, is a potent
activator of platelets while bivalirudin, a direct thrombin
inhibitor with a short half-life, has shown encouraging
results compared with UFH during PCI in terms of
bleeding reduction. However, the heparin regimen in the
control group was aggressive compared with current
practices.17 More recently, the investigators of REPLACE-2
described similar antithrombotic effects with bivalirudin
when compared with heparin in combination with GP
IIb-IIIa antagonists during PCI.18 In addition, bivalirudin
appears useful in patients with heparin-induced
thrombocytopenia.
Pretreatment with thienopyridines
A loading dose of 300 mg clopidogrel is recommended
before PCI,19 although such a pretreatment within
3 hours may not be sufficient. A higher initial dose of
600 mg establishes a greater level of platelet inhibition20
and can protect against myocardial injury in patients
undergoing PCI.21 It is currently recommended that
clopidogrel be administered as soon as possible in
patients with NSTE-ACS. The results from NSTE-ACS
may be extrapolated to ST-elevation myocardial
infarction (STEMI). Immediate administration of
clopidogrel (300 mg) appears more effective
(CLARITY-TIMI 28 study), as an adjunctive reperfusion
therapy when combined with fibrinolytics.22
Monitoring of antiplatelet activity
Numerous methods using flow cytometry or platelet
aggregometry are available for evaluation of biological efficiency of antiplatelet regimens. These might prove
helpful for monitoring efficacy of the treatment, but
there are not currently routinely recommended due to
the lack of standardization. In addition, specialised
laboratories are usually required. However, these tests
have shown important individual variability in the
degree of platelet inhibition induced by antiplatelet
therapy leading to the concept of ‘aspirin or clopidogrel
resistance’. One-third of patients treated by clopidogrel
appeared to be ‘unprotected’.23 Several mechanisms
have been suggested for this observation e.g. higher
platelet activity, variability in absorption or metabolism,
polymorphism of the P2Y12 platelet receptor.
Hypersensitivity to aspirin
A diagnosis of hypersensitivity to aspirin usually implies
complete exclusion of the molecule. Rapid aspirin
desensitization has been tested recently with a high
rate of success observed in patients with a history of
allergy to aspirin.24 Most of the patients underwent
uneventful coronary stenting under dual
antiplatelet therapy.
Antithrombotic therapy during primary PCI in
patients with STEMI
Aspirin (160–325 mg), UFH (50–70 UI/kg), and
clopidogrel (600 mg) should be administered as soon as
possible. The use of GP IIb-IIIa inhibitors during primary
PCI in patients with STEMI remains under debate.
Abciximab has been well investigated with some
significant results25,26 and pre-hospital treatment
seems logical in this setting.
Facilitated PCI during STEMI
Facilitated PCI is defined as planned intervention within
12 hours following the onset of symptoms and soon
after the administration of potent antithrombotic
agents (fibrinolytic agents and GPIIb-IIIa inhibitors)
alone or in association. So far, there is no evidence for
the recommendation of facilitated PCI. However, the
results of ongoing trials (FINESSE, ASSENT-4) may
change the current indications.
PCI after thrombolysis
If thrombolysis is preferred in patients with STEMI, it
should not be considered as the final treatment. Rescue
PCI after failed thrombolysis appears superior to
conservative treatment.27 ESC guidelines recommend
routine coronary angiography and – if needed – PCI
early (< 24 hours) post thrombolysis.2 Adequate
regimens are still to be defined in this setting where
too low or too high a degree of anticoagulation
may increase the risks of thrombotic and bleeding
complications.
Effects of contrast media on coagulation
Contrast media have anticoagulant properties of varying
intensity, depending on their chemical structure. In vitro
anticoagulant effects are more marked with ionic
agents.28 However, large multicentre randomised trials
showed that non-ionic contrast media do not increase
the risk of thromboembolic complications.29,30
Costs of antithrombotic therapy during PCI
Interventionists must take the cost and cost-effectiveness
of antithrombotic treatments into consideration,
including possible additional costs resulting from any
bleeding complications.31 Increased use of the radial
approach and development of arterial closure devices
has led to minimized risks of bleeding at the access site.
Economic evaluations can provide substantial
information supporting the choices between agents
with similar clinical impact.
Antithrombotic therapy and sheath removal
Use of low doses of heparin represents a major advance
in the last decade for the management of femoral
vascular access following PCI with stent placement.
Late sheath removal is associated with a higher rate of
bleeding and vascular events.32 Less aggressive
anticoagulation allows early and even immediate
sheath withdrawal after PCI performed via the
femoral route.33
Stent thrombosis
Despite the use of dual antiplatelet therapy and better
interventional techniques optimising stent implantation,
stent thrombosis has not been abolished (~1%). The
one-month incidence of subacute stent thrombosis
appears similar following the use of bare-metal stents
and drug-eluting stents in the real world.
34 Biological variations in the response to antiplatelet therapy are
potential causes of subacute stent thrombosis. An
increased platelet reactivity, which cannot be overcome
by ordinary antiplatelet therapy, has been described in
patients who suffered subacute stent thrombosis.35
Non-responders to antiplatelet treatment
The strategy for patients with insufficient platelet
inhibition with standard therapy remains unclear.
An increase in doses of clopidogrel (150 mg daily) or
use of another thienopyridine (ticlopidine) is the general
practice. An association between inadequate platelet
inhibition ex vivo and the risks of thrombotic
complications has yet to be demonstrated. Prasugrel, a
new molecule of the thienopyridine family currently
undergoing a Phase III clinical trial (TRITON TIMI-38), seems more effective in vitro at inhibiting platelet
aggregation than clopidogrel.36
Conclusion
As well as the meticulous intravascular techniques
necessary to minimize thromboembolic events, an
effective and safe antithrombotic therapy is needed
during PCI. Understanding of the roles of coagulation
and platelets in the complex process of thrombosis has
only evolved recently. Data supporting superior benefits
of new antithrombotic agents in the setting of PCI may
soon change the practices of interventionists. Moreover,
new management of ACS with earlier PCI leads to the
redefinition of most antithrombotic strategies.
The issue of non-responders to standard antiplatelet
therapy has probably been underestimated: simple
and reliable tests are needed to identify patients
insufficiently protected by antiplatelet therapy. In the
future, economic implications of ischaemic and bleeding
complications will guide the choice of antithrombotic
treatments for PCI. However, the implementation of
guidelines in antithrombotic therapy for PCI have yet to
be evaluated by contemporary surveys.
Key Learning
• PCI needs adequate antithrombotic therapy to limit thrombin generation and platelet activation
• Recently published recommendations on antithrombotic strategies during PCI are not homogeneous
• During PCI, use of LMWH remains debated and direct thrombin inhibitors are emerging
• Synergistic action of aspirin and thienopyridines has proved its efficiency after stent implantation
• Use of GP IIb-IIIa inhibitors in the real world conflicts with current recommendations
• Biological evaluation shows a large inter-individual variability in response to standard
antiplatelet therapy
• Abolition of subacute stent thrombosis remains a major challenge
• Some antithrombotic strategies should be redefined using contemporary practices
• Cost and cost-effectiveness of antithrombotic treatments will guide the interventionist’s
choices during PC |
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