Triple Therapy: Triple Threat?
Every patient who comes in with an acute coronary
syndrome (ACS) and undergoes PCI should be discharged on lifetime aspirin, right? Hard and fast rules
need to slow down a bit….
What about patients with AF who require PCI?
(FIGURE 3) This is fast becoming an unavoidable question for clinicians, since about 1% to 2% of the population has AF and 80% of them have an indication for
oral anticoagulants (OAC).8 Also, up to 30% of patients
with AF have coexistent vascular disease, with about
20% of those individuals requiring PCI over time. Before 2014, the guidelines recommended triple therapy
with a vitamin K antagonist, aspirin, and clopidogrel.
However, triple therapy is associated with an annual
bleeding risk of up to 45% and increased mortality.9
While the 2011 AF management guidelines suggested that low-dose aspirin and/or clopidogrel could
be given concurrently with anticoagulation,10 the newest iteration, released at the 2014 American College of
Cardiology Scientific Session, has clearly downgraded
aspirin use.11 The new 2014 AHA/ACC/HRS guidelines for the management of AF state: “Following
coronary revascularization (surgical or percutaneous)
in patients with AF and a CHA2DS2-VASc score of 2 or
greater, it may be reasonable to use clopidogrel (75 mg
once daily) concurrently with oral anticoagulation, but
without aspirin.”
“New evidence, including a randomized controlled trial and a real-life nationwide registry
of more than 12,000 patients, showed the great
potential of the combination of vitamin K antagonist
(VKA) and clopidogrel without aspirin to improve
clinical outcomes in comparison with triple therapy,”
wrote Willem J. M. Dewilde, MD, in a recent stateof-the-art review on triple therapy for AF patients undergoing PCI.9 Dr. Dewilde is from Amphia Hospital,
Breda, the Netherlands.
Dr. Dewilde and colleagues tentatively suggest that
a better option than dual therapy with warfarin and
clopidogrel may exist for patients with AF undergoing
PCI: warfarin and one of the new P2Y12 inhibitors,
either ticagrelor or prasugrel, both of which inhibit
platelets more
potently and show
less interindividual
variability than
is for
clopidogrel.
Aspirin
They cautioned,
however, that “we
The “A” in aspirin comes
do not have any
from acetylsalicylic acid,
data yet on the
the chemical name for
combination of
aspirin. The “spir” derives
VKA plus prasufrom the spirea plant, which
grel, VKA plus
is the type of plant that
ticagrelor, or triple
produces salicin, a natural
therapy (VKA
compound similar to acetylplus ticagrelor
salicylic acid, and “in” is
plus aspirin) in AF
just a common suffix for
patients undergomedications.
ing PCI, but one
A
46 CardioSource WorldNews
FIGURE 3
Double and Triple Antiplatelet Therapy
Risks in AF and PCI
Patients with AF who undergo PCI: combining antiplatelet and anticoagulant therapies in search of an optimal
equilibrium in between bleeding risk on the one hand
and thrombotic and thromboembolic risk on the other.
SOURCE: Ref. 9
could reasonably fear that combining these more
potent platelet inhibitors with VKA could lead to more
bleeding events.”
It so happens that the new 2014 AHA/ACC nonST-elevation-acute coronary syndrome (NSTE-ACS)
guidelines, published online September 23, 2014, for
the first time recommend one antiplatelet inhibitor
over another.12 (The guidelines are currently scheduled
to be published in the December 23, 2014, issue of
JACC.) Specifically, for early initial antiplatelet therapy
in patients with NSTE-ACS, ticagrelor is given a class
IIa recommendation over clopidogrel. Similarly, prior
to PCI, both ticagrelor and prasugrel are given class IIa
recommendations over clopidogrel, although prasugrel
carries a caveat that it should not be used in patients
who are at high risk for bleeding consistent with the
findings of TRITON-TIMI 38 trial.
For patients taking warfarin, the NSTE-ACS
guidelines suggest that triple therapy with warfarin,
clopidogrel, and aspirin should be of limited duration
to reduce bleeding risk, and that a proton pump inhibitor should be used for those with a history of gastrointestinal (GI) bleeding and considered for those without
such a history.
The guidelines also recommend limiting the duration of triple antithrombotic therapy with a vitamin
K antagonist, aspirin, and a P2Y12 receptor inhibitor
in patients with NSTE-ACS to reduce bleeding risk,
adding that there is “sparse information” on the use of
the newer P2Y12 inhibitors in patients receiving triple
therapy.
Of note, ticagrelor carries a Black Box warning
stating: “Maintenance doses of aspirin above 100 mg
reduce the effectiveness of ticagrelor and should be
avoided. After any initial loading dose, use with aspirin
75-100 mg/day.” For both prasugrel and clopidogrel,
the package insert notes maintenance daily aspirin can
be from 100 to 350 mg.
The NSTE-ACS guideline authors do specify that
the recommended maintenance dose of aspirin to be
used with ticagrelor is 81 mg/day, and, elsewhere, state
that after PCI, “it is reasonable to use 81 mg per day of
aspirin in preference to higher maintenance doses.”
New and Improved: Do NOACs and Aspirin
Play Well Together?
At present, there are no published trials to have
directly evaluated the use of NOACs in patients with
ACS and AF on dual antiplatelet therapy. Post hoc and
planned analyses of the randomized controlled trials of
NOACs in nonvalvular AF have indicated that bleeding
risk is elevated in patients taking concomitant aspirin,
consistent with the known risks of aspirin.13,14
However, at press time for this issue, investigators reported in JAMA Internal Medicine a higher than
expected risk of bleeding in patients recently initiated
on dabigatran.15 Hernandez et al. used pharmacy and
medical claims from a 5% random sample of Medicare
beneficiaries who had initiated therapy with dabigatran or warfarin within 60 days of AF diagnosis.
Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30
(95% CI, 1.20 to 1.41) for any bleeding event, 1.58
(95% CI, 1.36 to 1.83) for major bleeding, and 1.85
(95% CI, 1.64 to 2.07) for GI bleeding. Dabigatran
was consistently associated with an increased risk of
major bleeding and GI hemorrhage for all subgroups
analyzed. The risk of major bleeding among dabigatran
users was especially high for African Americans and
patients with chronic kidney disease. One piece of
good news: risk of intracranial hemorrhage was lower
with dabigatran.
In an accompanying commentary, journal editorin-chief Rita Redberg, MD, wrote that these findings
“give us cause for concern because it appears that the
bleeding risk for dabigatran is higher than for warfarin
and significantly greater than originally appeared at
the time of the FDA approval.”16
Christopher Cannon, MD, Executive Director of
Cardiometabolic Trials at Harvard Clinical Research
Institute had a different take on the results. “On dabigatran, t he news was higher bleeding – from one of 2
studies. The data were actually very reassuring (given
that) the FDA safety review came to the opposite conclusion: dabigatran’s safety profile was reaffirmed.”
Having said that, he added, that since the results
of the 2013 WOEST study,17 “I do think of clopidogrel
and OACs much more without aspirin. We have all
been searching for approaches to reduce the bleeding
of triple therapy and WOEST gave the first glimmer
of hope.” That trial showed clopiogrel without aspirin
was associated with a significant reduction in bleeding
complications but no increase in the rate of thrombotic
events in patients on OAC who have undergone PCI.
One slight additional complicating factor: the increasing use of the new P2Y12 inhibitors “would be expected to expose the patients to an even higher risk of
December 2014