Download When and how to discontinue antiplatelet therapy

European Heart Journal Supplements (2008) 10 (Supplement A), A35–A41
doi:10.1093/eurheartj/sum082
When and how to discontinue antiplatelet therapy
Michel E. Bertrand*
Hôpital Cardiologique, Boulevard du Pr Leclercq, Lille 59037, France
KEYWORDS
Aspirin;
Clopidogrel;
Bleeding;
Stroke;
Thrombosis;
Acute coronary syndromes
Antiplatelet agents reduce the risk of ischaemic events but increase the risk of bleeding. When cardiac patients on antiplatelet therapy require surgery or invasive diagnostic procedures, a decision must be made whether or not to discontinue antiplatelet
therapy. Because there is little evidence from clinical trials that would aid in the formulation of comprehensive recommendations, the decision must be made on an individual basis. The patient’s inherent risk for bleeding, concomitant treatments that
may increase this risk, the potential of the procedure to cause bleeding, and the
patient’s risk for ischaemic events if antiplatelet therapy is stopped all must be considered. Some procedures carry a low risk of bleeding and can be carried out in most
patients without discontinuing antiplatelet therapy, whereas others require close
evaluation and risk stratification of the patient. Patients on antiplatelet therapy
undergoing cardiac surgery, those with drug-eluting stents, and those on anticoagulation require particularly careful management. There is an urgent need for research
into this complex clinical problem.
Introduction
Antiplatelet agents—principally aspirin and clopidogrel,
used alone or in combination—have been shown to
reduce the risk of myocardial infarction (MI), ischaemic
stroke, and cardiovascular death in patients with
unstable angina, non–ST-elevation (NSTE)-acute coronary
syndromes (ACS), and ST-elevation MI (STEMI).1–10 In
patients at risk, aspirin is recommended as life-long
therapy and clopidogrel is recommended for periods
ranging from 1 to 12 months, or as a life-long substitute
for aspirin in patients in whom aspirin is contraindicated.11–14 As a result, antiplatelet agents have become
essential components of the treatment of these conditions. The most serious adverse effect associated with
use of antiplatelet agents is bleeding.15 This raises the
question of whether and, if so, when to discontinue antiplatelet therapy in patients who need surgery or diagnostic procedures that carry a risk of tissue injury. The
question is important because discontinuation of antiplatelet agents results in recovery of platelet function,
which contributes to the occurrence of ischaemic
* Corresponding author. Tel: þ33 320 92 13 34; fax: þ33 320 00 65 09.
E-mail address: [email protected]
events.16–18 Unfortunately, neither good evidence from
clinical trials nor authoritative guidelines are available
to guide physicians faced with this dilemma. This
article will review what is known about discontinuation
of antiplatelet agents and suggest approaches to help
physicians care for patients in this setting.
Risk factors for bleeding and ischaemic
events
Deciding whether to discontinue antiplatelet agents is a
matter of weighing the risk of bleeding against the risk
of ischaemic events. Several factors must be considered:
the patient’s inherent risk for bleeding; ongoing treatments that may increase that risk; the potential of the
procedure being contemplated to cause bleeding; and
the risk of an ischaemic event if the antiplatelet
therapy is stopped.
Inherent bleeding risk
Identification of patients at high risk for bleeding is the
first step in managing those on antiplatelet agents who
require invasive procedures. Demographic factors that
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007.
For permissions please email: [email protected].
A36
increase the likelihood of bleeding are advanced age and
female sex; a history of bleeding events, haemorrhagic
peptic ulcer, or haemorrhagic stroke also should alert
physicians to the possibility of bleeding.19 Medical conditions that increase the risk of bleeding include
obesity, diabetes, hypertension, renal impairment or
failure, heart failure, other major organ dysfunction,
and haemostatic disorders.19,20 A multivariate regression
model based on data from the Global Registry of Acute
Coronary Events can be used to identify patients with
STEMI, non–ST-elevation MI (NSTEMI), or unstable
angina who are at high risk for bleeding.21 Significant
predictors of bleeding risk in this model include female
sex, renal insufficiency, history of bleeding, and, most
importantly, advanced age.
Treatments that increase bleeding risk
Concomitant anticoagulant or fibrinolytic drug therapy
increases bleeding risk to a greater or lesser extent
depending on the drug used, its dose, the duration of
treatment, and the timing of administration in relation
to the procedure.20
Procedures that increase bleeding risk
With the invasive procedures that coronary patients are
most likely to undergo, such as angiography, intra-aortic
balloon pump placement, coronary artery bypass grafting
(CABG), and percutaneous coronary intervention (PCI),
there is a lower risk of bleeding and it is relatively easy
to manage if it occurs, particularly in the case of PCI
with a femoral approach rather than a radial approach.20
Risks associated with discontinuation
Retrospective studies show that discontinuation of aspirin
therapy puts patients at risk for MI and stroke.16–18
Patients at particularly high risk are those with recent or
recurrent ACS with dual oral antiplatelet therapy, recent
PCI, left ventricular ejection fraction 30%, tri-vessel
disease, stent of length .25 mm or, especially, a
drug-eluting stent (DES), history of thrombosis in a vessel
of diameter 2.5 mm, incomplete revascularization, and
2 locations of symptomatic atherothrombosis.19
Other considerations
Complicating this issue is that some of the factors that
put patients at high risk of bleeding also put them at
risk of ischaemic events. These include the demographic
factors of advanced age and female sex and medical
factors such as obesity, diabetes, heart failure, and
renal failure.19 Patients with these conditions present a
particularly difficult dilemma for clinicians.
Further compounding the problem of knowing when to
discontinue antiplatelet therapy is the fact that many of
the conditions that put patients at high risk for bleeding
are exclusion criteria in clinical trials of antiplatelet
agents.19 Thus, data on patients with these conditions
are not found in the medical literature. A unified,
M.E. Bertrand
validated method of sorting and scoring patients in
terms of their bleeding risk and weighing it against
their risk of ischaemic events is sorely needed but is as
yet unavailable.
Recommendations for patients undergoing
invasive procedures
Endoscopy
Some evidence is available to guide clinicians performing
endoscopic procedures in patients on antiplatelet
therapy. A retrospective case-control study of patients
who underwent endoscopic sphincterotomy recruited 40
patients who bled following the procedure and 86 ageand sex-matched controls who did not.22 After adjusting
for confounding factors, the authors found no association
between use of antiplatelet agents and post-procedural
bleeding, although there were too few patients taking
clopidogrel to draw any conclusion regarding its use.
A review of 5593 patients who underwent colonoscopy
included 1657 patients in whom polypectomy was performed.23 Immediate bleeding occurred in 32 patients
and delayed bleeding occurred in five patients. Although
use of the anticoagulant warfarin was associated with a
significantly higher risk of bleeding, use of antiplatelet
agents was not.
Nevertheless, because of the lack of controlled clinical
trials studying this issue, some authors recommend discontinuing antiplatelet agents before colonoscopy,
sphincterotomy, oesophageal dilation, and endoscopic
ultrasound-guided biopsy or drainage.24
Guidelines from the French Society for Digestive Endoscopy classify endoscopic procedures into three groups.25
The first group includes those with a low risk of bleeding,
in which bleeding can be controlled endoscopically; this
group includes gastroscopy, rectosigmoidoscopy, and
colonoscopy without polypectomy. The second group
includes procedures with a high risk of bleeding (1%),
also with the possibility of endoscopic control, including
colonic polypectomy, gastric macro-biopsy with loop
polypectomy and gastric polypectomy, and endoscopic
sphincterotomy. The third group includes procedures
with a low risk of bleeding, but without the possibility
of endoscopic control; endoscopic ultrasound fine-needle
aspiration and percutaneous gastrostomy fall into this
group.
Given its relatively low potential to contribute to
serious bleeding, there is no need to discontinue aspirin
in most patients undergoing procedures in the first
group; even colonoscopy with polypectomy is probably
safe absent other risk factors for bleeding.25 Aspirin
should be discontinued before procedures in the second
and third groups, or if possible, the procedure should
be postponed until the risks related to aspirin discontinuation are lower.25 There are insufficient data to
extrapolate these recommendations to patients taking
thienopyridines.25
Guidelines from the American Society for Gastrointestinal Endoscopy recommend discontinuing thienopyridines
When and how to discontinue antiplatelet therapy
7–10 days before procedures associated with a high risk for
bleeding, including polypectomy, biliary sphincterotomy,
pneumatic or bougie dilation, and percutaneous endoscopic gastrostomy.26
Dental procedures
A literature review and guideline development process
conducted by the Oral Medicine and Oral Surgery Francophone Society found that, based on agreement among
professionals in the field, interruption of aspirin or
thienopyridine therapy before dental procedures is
unnecessary.27 Most such procedures carry a low risk of
bleeding, and any bleeding that occurs can usually be
controlled by local haemostasis.
Recommendations for patients undergoing
surgery
Surgical procedures in which discontinuation
of antiplatelet therapy is unnecessary
In general, discontinuation of antiplatelet therapy is considered unnecessary in procedures that are not highly
invasive and therefore have a low bleeding risk. Several
small studies have found no excess of bleeding among
patients taking aspirin who underwent dermatologic
surgery.28–30 One study found a greater likelihood of
bleeding among patients taking aspirin who had prolonged bleeding times, but it was easily controlled with
standard measures.31 Little evidence is available regarding the effects of thienopyridines in patients undergoing
dermatologic surgery.32
The French Society of Anesthesiology and Intensive
Care (SFAR) considers discontinuation of aspirin
unnecessary before ophthalmologic surgery.33 Because
aspirin and clopidogrel have additive effects on bleeding
time, a suggestion has been made to continue aspirin but
discontinue clopidogrel before ophthalmologic surgery in
patients on combination therapy.34
Oral, periodontal, and implant dental surgery are not
associated with high rates of bleeding. Any bleeding
that occurs can usually be controlled locally, so discontinuation of aspirin is not recommended.27
Aspirin therapy is recommended before carotid endarterectomy to reduce the risk of peri-operative coronary
events35 and has not been found to increase bleeding
risk during the procedure.33 A decision model suggested
that aspirin therapy before infrainguinal revascularization surgery would increase the incidence of minor bleeding but that this would be far outweighed by a reduction
in mortality and an increase in quality-adjusted life
expectancy.36
Surgical procedures in which discontinuation
of antiplatelet therapy is recommended
SFAR has identified procedures before which aspirin
therapy should be discontinued because of a significantly
increased bleeding risk.33 There is a high degree of
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certainty that even low aspirin doses before hip surgery
increase the risk of haemorrhage and the need for transfusion, but post-operative aspirin poses no risk in hip or
knee surgery. In tonsillectomy, pre- or post-operative
aspirin may contribute to peri-operative bleeding and
increase the number of revision procedures for haemostasis. Ticlopidine, one of the thienopyridine antiplatelet
agents, should be discontinued before transurethral
resection of the prostate; whether aspirin should be discontinued is uncertain. Prostate surgery via the abdominal approach requires discontinuation of aspirin.
Cardiac surgery
Although surgical haemostasis can be controlled during
cardiac surgery, it is a special case in the decision
whether to discontinue antiplatelet therapy. It carries a
high risk of bleeding, but the patient is by definition at
high risk for ischaemic events. Although aspirin can be
continued in patients undergoing cardiac surgery, clopidogrel should be stopped at least 5 days before the procedure when the surgery is scheduled and the risk of
ischaemia is low.11,37
In the CURE trial, which compared clopidogrel and
placebo in patients with NSTE-ACS, study medication
was discontinued in most patients who underwent
CABG.4 There was no difference in bleeding between
placebo patients and clopidogrel patients whose medication was discontinued 5 days before surgery, but a
significantly higher rate of bleeding occurred in patients
whose clopidogrel was discontinued 5 days before
surgery (9.6% in the clopidogrel group vs. 6.3% in the
placebo group, P ¼ 0.06).
A recent prospective observational study of 217
patients scheduled for first-time CABG surgery examined
the bleeding risks associated with continuing clopidogrel
therapy until surgery.38 Patients were treated either with
aspirin alone or aspirin combined with clopidogrel for
5 days before surgery. All received prophylactic low-dose
aprotinin. Maintenance of clopidogrel therapy until
surgery was not associated with increased post-operative
bleeding or transfusion rates.
Management of oral antiplatelet therapy
in patients undergoing surgery
Little evidence is available and comprehensive guidelines
have not been developed to determine how to manage
antiplatelet therapy in surgical patients. As a practical
matter, the surgeon, cardiologist, haematologist, and
anaesthesiologist should consult on each case regarding
the risk of peri-operative bleeding if antiplatelet
therapy is continued and the risk of ischaemic events if
therapy is discontinued.37 If neither course is acceptable,
postponement of the surgery should be considered, if
possible.
In its review of the literature, the Task Force on the
Management of Acute Coronary Syndromes of the
European Society of Cardiology (ESC) found a relatively
low risk of bleeding during CABG in patients whose
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M.E. Bertrand
antiplatelet therapy had not been discontinued .5 days
before surgery.11 Nevertheless, in the interests of
caution, the Task Force recommended that in patients
with a low risk of progressing to MI or death, oral antiplatelet agents should be discontinued 5 days before
the procedure and reinstituted as soon as possible thereafter. Surgical measures to minimize bleeding and platelet
transfusions may be required in such cases.
A balanced approach to managing antiplatelet therapy
in surgical patients is being addressed in the ongoing
STRATAGEM trial, which will recruit 1500 patients
with symptomatic stable atherothrombotic disease
receiving antiplatelet therapy who are scheduled for noncoronary surgery.39 Ten days before surgery, patients will
discontinue their current antiplatelet regimen and be
randomized to receive aspirin 75 mg/day or placebo
until surgery. It is hoped that this low-dose antiplatelet
regimen will protect against peri-operative ischaemic
events without an increase in bleeding.
Patients with drug-eluting stents
undergoing surgery
The presence of a DES adds another consideration when a
patient on antiplatelet therapy needs surgery. In the ESC
guidelines for PCI, dual antiplatelet therapy is recommended in patients with DESs for a period of 6–12
months after stent placement,40 but more recently the
U.S. Food and Drug Administration recommended dual
antiplatelet treatment for 12 months.41 Discontinuation
of antiplatelet therapy is associated with increased
rates of stent thrombosis.42–44 If possible, at least 2–4
weeks should elapse between placement of a stent and
major non-cardiac surgery.45 If surgery cannot be postponed, the recommendations of an SFAR task force may
be helpful (Table 1).37 Patients who are at high risk of
stent thrombosis should be identified, including those
with a history of stent thrombosis; those with .1 stent,
long stents, a stent placed at a bifurcation, a stent in
the left main artery or in small arteries, or incomplete
revascularization; and those who have complicating conditions such as diabetes, heart failure, or low ejection
fraction. If the patient is not at high risk of bleeding
and if the surgery is not associated with significant
blood loss, aspirin therapy should be continued. Thienopyridine discontinuation 5 days before the procedure
should be considered on a case-by-case basis. If there is
a high risk of bleeding, withdrawal of both agents
should be considered. If surgery is urgent or cannot be
postponed for 5 days, discontinuation will not be possible
or effective at the time of surgery and optimal surgical
and pharmacological haemostasis must be employed. If
clopidogrel is discontinued before surgery, resuming
therapy with a 300-mg loading dose may be considered.
If aspirin is discontinued, resuming with a loading dose
.160 mg may be considered. Although the task force
suggested substituting non-steroidal anti-inflammatory
agents or heparin for antiplatelet agents, the efficacy
of the former and the safety of the latter have been
questioned.19,37
Treatment of acute bleeding
If bleeding occurs in a surgical patient whose antiplatelet
therapy has not been discontinued, all antiplatelet drugs
should be stopped immediately. The principles of
managing major bleeding remain the same, and should
include intravenous fluid, transfusion of packed red
blood cells, and whatever surgical or other measures
are necessary.20 If the bleeding is gastrointestinal and
can be controlled with endoscopic injection and
Table 1 Recommendations of the French Society of Anesthesiology and Intensive Care (SFAR) regarding management of antiplatelet
therapy in patients with drug-eluting stents (DESs). Interventions must be postponed 6 weeks after an acute coronary event37
Risk of stent thrombosis (to
be evaluated with the
cardiologist)a
Major
Moderate
Haemorrhagic risk of the invasive or surgical procedure (to be evaluated with the physician or the
surgeon)b
Major
Intermediate
Minor
Postpone intervention 6 months to
1 year after stent positioning
Postpone intervention
6 months to 1 year after
stent positioning
If impossible: maintain
aspirin, stop clopidogrel
5 days
Maintain aspirin, stop
clopidogrel 5 days
Maintain aspirin and
clopidogrel
If impossible: stop aspirin–clopidogrel
5 days, or stop aspirin–clopidogrel
10 days (max) and substitute
Stop aspirin–clopidogrel 5 days, or
stop aspirin–clopidogrel 10 days
(max) and substitute
Maintain aspirin and
clopidogrel, or maintain
aspirin and stop clopidogrel
5 days
Adapted with permission from Oxford University Press. From Albaladejo et al., Br J Anaesth 2006;97:580–582; permission conveyed through Copyright Clearance Center, Inc.
a
Risk of stent thrombosis—major: stent in place ,6 months to 1 year or patient requiring aspirin and clopidogrel or patient with risk factor; moderate: stent in place .6 months to 1 year.
b
Haemorrhagic risk – major: intervention cannot proceed on antiplatelet agent; intermediate: intervention can proceed on aspirin alone; minor:
intervention can proceed on aspirin and clopidogrel.
When and how to discontinue antiplatelet therapy
A39
mechanical means, discontinuation of antiplatelet agents
may not be necessary, especially in patients at high risk
for thrombosis.20
Antiplatelet therapy in patients on
anticoagulation undergoing percutaneous
coronary intervention with stenting
not to prolong aspirin and clopidogrel therapy beyond
that recommended in clinical guidelines. Use of a baremetal stent, rather than a DES, will shorten the required
period of dual antiplatelet therapy, and a radial
approach, rather than a femoral approach, will reduce
the risk of bleeding.
The role of emerging antiplatelet therapies
Anticoagulants are routinely prescribed for patients with
atrial fibrillation or prosthetic heart valves, who may also
have coronary atherosclerosis treated with antiplatelet
agents. Given concomitantly, warfarin and antiplatelet
agents confer a high risk of bleeding.46,47 How these
patients should be managed if they require PCI with
stenting is uncertain, and there is much variability in
their care.48,49 Various recommendations have been
made, most of them based on an evaluation of the
patient’s relative risks of ischaemic events and bleeding
and the need to provide antiplatelet agents in sufficient
doses for a long-enough period to prevent the former
without triggering the latter (Table 2).46,49,50 If warfarin
is to be continued, it would at least seem reasonable
The practicality of clopidogrel therapy is limited by its
irreversible effects and slow onset of action. If discontinuation is necessary, platelet function does not fully recover
for at least several days; when therapy is resumed, protection against thrombosis is delayed. Newer antiplatelet
agents may help overcome some of these limitations.
AZD6140 and cangrelor are reversible antiplatelet agents
that could be discontinued much sooner prior to surgery
than clopidogrel, thus easing patient management and
reducing the risk of bleeding when surgery is urgent.51,52
Prasugrel, a thienopyridine with irreversible antiplatelet
effects, has a faster onset of action, greater potency,
and less variability in response than clopidogrel and
Table 2 Suggested management strategy for patients with non-valvular atrial fibrillation requiring anticoagulation and
percutaneous coronary intervention (PCI) with stenting49a
Stroke risk
category
Usual strategy
recommended
Low
Aspirin
High
Warfarin
High
Warfarin
Perceived
potential
bleeding risk
Acute coronary
syndrome (ACS)
presentation
Low
No
Low
Yes
Highb
No
Highb
Yes
Post-PCI management
BMS: aspirin plus clopidogrel for 4 weeks, then
aspirin
DES: aspirin plus clopidogrel for 6–12 months,
then aspirin
BMS if possible
BMS: triple therapy with warfarin, aspirin, and
clopidogrel for 2–4 weeks; then warfarin plus
clopidogrel up to month 12; then warfarin alone
DES: triple therapy with warfarin, aspirin, and
clopidogrel for 3–6 months or more; then
warfarin plus clopidogrel up to month 12; then
warfarin alone
BMS or DES: triple therapy with warfarin, aspirin,
and clopidogrel for 3–6 months or more; then
warfarin plus clopidogrel up to month 12; then
warfarin alone
BMS if possible
BMS: triple therapy with warfarin, aspirin, and
clopidogrel for 4 weeks, then warfarin alone
DES: triple therapy with warfarin, aspirin, and
clopidogrel for 4 weeks; then warfarin plus
clopidogrel up to month 12; then warfarin alone
BMS or DES: triple therapy with warfarin, aspirin,
and clopidogrel for 4 weeks; then warfarin plus
clopidogrel up to month 12; then warfarin alone
BMS, bare metal stent; DES, drug-eluting stent.
Adapted with permission from American College of Chest Physicians. From Lip, Karpha, Chest 2006;130:1823–1827; permission conveyed through
Copyright Clearance Center, Inc.
a
Doses: aspirin, 75–81 mg/day; clopidogrel, 75 mg/day. Warfarin is dose adjusted to target international normalized ratio (INR) of 2.0–2.5.
b
Particular attention should be paid to patients with any of the following risk factors: (i) aged .75 years; (ii) receiving non-steroidal antiinflammatory drugs; (iii) receiving multiple other drug treatments; (iv) uncontrolled hypertension; (v) history of bleeding (e.g. peptic ulcer, cerebral
haemorrhage); and (vi) history of poorly controlled anticoagulation therapy.
A40
might be expected to provide more rapid protection
against thrombosis when therapy is resumed.53 The
recent TRITON-TIMI 38 trial, which compared prasugrel
with clopidogrel in patients with moderate- to high-risk
ACS, found that prasugrel therapy was associated with a
lower rate of death from cardiovascular causes, nonfatal
MI, or nonfatal stroke and a higher rate of major bleeding,
including fatal bleeding.54 The ongoing PRINCIPLE55 and
ACAPULCO56 trials will further define the differences in
these drugs’ clinical effects.
Conclusion
The decision whether to discontinue antiplatelet therapy
in a coronary patient who needs surgery or a diagnostic
procedure is based on an evaluation of the patient’s
risk for bleeding and risk for ischaemic events. Unfortunately, with a few exceptions, each case must be
decided individually because there is insufficient clinical
evidence to establish comprehensive guidelines. Discontinuation of antiplatelet therapy appears to carry real
challenges and continuation of antiplatelet therapy
should be the rule when the risk of bleeding is low or haemostasis is controllable. If a procedure is associated with
a high risk of bleeding, consideration should be given to
postponing it; if that is not possible, antiplatelet agents
should be discontinued only if necessary and reinstated
promptly. There is an urgent need for research on this
issue with the goal of establishing a comprehensive set
of recommendations.
Conflict of interest: None declared.
Funding
Sponsored by an educational grant from Daiichi Sankyo Europe
GmbH and Eli Lilly and Company.
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