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Recommendations for
Antiplatelet Agents |
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COR |
LOE |
Recommendations |
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I |
A |
Antiplatelet therapy with aspirin
alone (range 75–325 mg per day) or clopidogrel alone (75
mg per day) is recommended to reduce MI, stroke, and vascular
death in patients with symptomatic PAD.
139–142
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See Online Data Supplement
13. |
The effect of antiplatelet therapy on
cardiovascular events has been systematically reviewed by the
Antithrombotic Trialists' Collaboration.139 Of note, this
meta-analysis included studies of antiplatelet agents other than
aspirin or clopidogrel. Among patients with symptomatic PAD treated
with antiplatelet therapy, there was a 22% odds reduction
for cardiovascular events, including MI, stroke, or vascular
death.139
Symptomatic patients with lower extremity PAD included both those
with claudication and those with prior lower extremity
revascularization. The Antithrombotic Trialists'
Collaboration meta-analysis also compared the efficacy of different
doses of aspirin.139 The proportional reduction in vascular events
was 32% with 75 to 150 mg daily, 26% with 160 to 325
mg daily, and 19% with 500 to 1500 mg daily, whereas there
was a significantly smaller (13%) reduction in
cardiovascular events in patients being treated with <75 mg
of aspirin per day.139 CLIPS (Critical Leg Ischaemia Prevention
Study) demonstrated a benefit of aspirin (100 mg daily) compared
with placebo in preventing vascular events, but the study was too
small to derive meaningful conclusions.140 A meta-analysis of trials
of aspirin (alone or in combination with dipyridamole) for
prevention of cardiovascular events in patients with PAD found a
non–statistically significant reduction in the primary
endpoint of cardiovascular death, MI, and stroke and a statistically
significant reduction in the secondary endpoint of nonfatal stroke
with aspirin versus placebo.141 The CAPRIE (Clopidogrel Versus Aspirin in
Patients at Risk of Ischemic Events) trial demonstrated a benefit of
clopidogrel as compared with aspirin in cardiovascular risk
reduction and bleeding events in a population of patients with
symptomatic atherosclerotic vascular disease, including a subgroup
of patients with symptomatic PAD.142
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IIa |
C-EO |
In asymptomatic patients with PAD
(ABI ≤0.90), antiplatelet therapy is reasonable to
reduce the risk of MI, stroke, or vascular death. |
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See Online Data Supplement
13. |
Patients with PAD (ie, ABI
≤0.90) who do not have claudication may have leg symptoms
atypical for claudication or may be too functionally limited to
allow for adequate leg symptom assessment. Patients with PAD without
claudication are at increased cardiovascular risk.79 Subgroup analysis
in a trial evaluating asymptomatic patients did not show an effect
of aspirin in patients with an abnormally low ABI (<0.80 or
≤0.90).76 However, the trial was not powered to
analyze subgroups, and the uncertainty of the result does not rule
out the possibility that aspirin could provide benefit in such
patients, especially in those at increased risk of cardiovascular
events. Another trial that included asymptomatic patients was too
small to derive meaningful conclusions.140
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IIb |
B-R |
In asymptomatic patients with
borderline ABI (0.91–0.99), the usefulness of
antiplatelet therapy to reduce the risk of MI, stroke, or
vascular death is uncertain.75,76
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See Online Data Supplement
13. |
In asymptomatic patients with an
abnormal or borderline ABI, 2 RCTs found that aspirin had no effect
in reducing cardiovascular events75,76 and might increase bleeding.76 However, the
trials were not powered to examine patients with borderline ABI
separately. Given that cardiovascular risk is lower in patients with
borderline ABI than in those with abnormal ABI,80 it would be unlikely that
aspirin would have a meaningful effect in this subgroup when there
was no evidence of an effect in the total trial populations. |
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IIb |
B-R |
The effectiveness of dual
antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce
the risk of cardiovascular ischemic events in patients with
symptomatic PAD is not well established.143,144
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See Online Data Supplement
13. |
Based on findings from a subset of
patients with PAD in the CHARISMA (Clopidogrel for High
Atherothrombotic Risk and Ischemic Stabilization, Management, and
Avoidance) trial, DAPT with aspirin plus clopidogrel may be
considered for patients with PAD at particularly high risk of
cardiovascular ischemic events who are not at high risk of
bleeding.143,144 Currently, there are sparse data on newer
P2Y12 antagonists for PAD. There is uncertainty about
the net benefit of long-term DAPT for patients with
PAD—specifically the balance of risks of cardiovascular
ischemic events versus major bleeding. Additional clinical trials
are needed in the population with PAD. Refer to the DAPT guideline
focused update for DAPT recommendations specifically for
CAD.20
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IIb |
C-LD |
DAPT (aspirin and clopidogrel)
may be reasonable to reduce the risk of limb-related events in
patients with symptomatic PAD after lower extremity
revascularization.145–148
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See Online Data Supplements 13 and
14. |
There are sparse data on DAPT after
lower extremity revascularization. Still, DAPT is prescribed in up
to 55% of patients after endovascular revascularization for
CLI.146
One small RCT of aspirin or aspirin plus clopidogrel in patients
undergoing endovascular revascularization demonstrated that patients
with DAPT had fewer repeat revascularization procedures for clinical
symptoms.145 A subsequent small RCT of aspirin plus placebo
or aspirin plus clopidogrel in patients after endovascular
revascularization also showed a decrease in the need for repeat
revascularization at 6 months in patients receiving
clopidogrel.147 An RCT of aspirin plus placebo or aspirin plus
clopidogrel in patients who underwent below-knee bypass graft showed
a decrease in limb-related events only in the prespecified subgroup
of patients with prosthetic bypass grafts.148 Refer to the DAPT guideline
focused update for DAPT recommendations specifically for
CAD.20
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IIb |
B-R |
The overall clinical benefit of
vorapaxar added to existing antiplatelet therapy in patients
with symptomatic PAD is uncertain.149–152
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See Online Data Supplement
13. |
This novel antagonist of
protease-activated receptor-1 added to existing antiplatelet therapy
reduced the risk of cardiovascular ischemic events in patients with
atherosclerosis who were receiving standard therapy in an
RCT.150,151 However, it also
increased the risk of moderate or severe bleeding. Although the
cardiovascular benefit was not demonstrated in the subgroup with
symptomatic PAD, there was a reduction in limb-related events with
vorapaxar, specifically in acute limb ischemia (ALI) and peripheral
revascularization.149,152 More than half of ALI events in the PAD subset
were due to thrombosis of lower extremity bypass grafts.149 Unfortunately,
the benefit in limb events in patients with PAD was accompanied by
an increased risk of bleeding.149,152 Therefore, the overall clinical benefit of
vorapaxar in patients with PAD is uncertain. |
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