-
113
Atrial fibrillation (AF), the most common cardiac arrhyth-mia,
occurs in 1% to 2% of the general population, with a prevalence
varying from 0.5% in subjects 40 to 50 years old to 5% to 15% in
the elderly who are >80 years old.13 Stroke is the most feared
complication of AF, resulting in death or disabling symptoms in a
vast proportion of cases.4 In the Framingham study, the
age-adjusted incidence of stroke was 5-fold higher in subjects with
AF, and the attributable risk raised from 1.5% at 50 to 59 years to
23.5% at 80 to 89 years.5
Chronic oral anticoagulation (OAC) therapy is the main-stay of
stroke prevention in patients with AF at high risk for
cardioembolic sequelae; 70% to 80% of all patients with AF have an
indication for OAC, and coronary artery dis-ease coexists in 20% to
30% of them.6,7 With an estimated prevalence of AF in 1% to 2% of
the population, it may be projected that 1 to 2 million patients on
OAC in both the United States and Europe are candidates for
coronary revas-cularization, often in the form of percutaneous
coronary interventions (PCI). Patients undergoing PCI, as well as
those who present with an acute coronary syndrome (ACS), also
require dual antiplatelet therapy (DAPT), usually aspi-rin in
combination with a platelet adenosine diphosphate P2Y
12 receptor antagonist, with the goal of reducing the
risk of ischemic recurrences, including stent thrombosis.8
However, the efficacy and safety of combining OAC with DAPT (triple
antithrombotic therapy) in these patients is a topic of debate. In
fact, although this combination can poten-tially prevent both
thromboembolism and atherothrombotic events, it is also associated
with an increased risk of severe bleeding. In a large nationwide
registry of 40 812 patients hospitalized with myocardial infarction
(MI), the risk of subsequent hospitalizations for bleeding
increased with the number of antithrombotic drugs used, being
1.8-fold in patients on vitamin K antagonists (VKAs) and aspirin,
3.5-fold in patients on VKAs and clopidogrel, and 4-fold in
patients on triple therapy, with numbers needed to harm of 45.4,
15.2, and 12.5, respectively.9 On this background, treatment with
OAC and antiplatelet agents requires careful
consideration of the risks and benefits associated with each
drug and their combination.
On one hand, the challenge of balancing the risk of
throm-boembolism (ie, stroke) and atherothrombotic events (ie,
stent thrombosis) and, on the other, the risk of bleeding demand
for a timely review of the literature on using various
com-binations of OAC and antiplatelet therapies in patients with
coexisting AF and coronary artery disease. This is also
under-scored by the recent availability of newer antithrombotic
agents, including oral anticoagulants (ie, dabigatran,
rivarox-aban, apixaban) and antiplatelets (ie, prasugrel,
ticagrelor). This article reviews the evidence supporting
antithrombotic agents for AF and ACS/PCI, and describes
contemporary antithrombotic regimens and practical recommendations
for patients with both conditions, with focus on new data and
ongoing development of novel oral anticoagulant (NOAC) and
antiplatelet drugs.
Epidemiology of Relevant Clinical ScenariosTriple antithrombotic
therapy may be required as the result of several commonly
encountered clinical scenarios in daily practice. First, patients
with paroxysmal, persistent, long- standing, or permanent AF on OAC
may experience an ACS, either nonST-segment elevation ACS
(NSTE-ACS) or ST-segment elevation MI, or undergo elective PCI. In
a prospec-tive series of 261 consecutive patients with AF
undergoing coronary angiography, the overall incidence of coronary
artery disease was relatively high at 34%, and revascularization by
either PCI or coronary artery bypass grafting was needed in 21%.10
Second, new-onset AF may occur within 7 days dur-ing or after
hospitalization in 6% to 8% of patients after an ACS or PCI.1114 In
a meta-analysis of 120 566 patients from 10 clinical trials, AF
occurred in 8% of patients with a ST-seg-ment elevation MI and in
6.4% of patients with NSTE-ACS.15 Importantly, 7-day mortality was
higher in patients with AF (5.1%) than in those without AF (1.6%),
with adjusted hazards of 1.65 in ST-segment elevation MI and 2.30
in NSTE-ACS. At present, the underlying mechanisms of AF in
myocardial ischemia remain poorly understood.16
(Circ Cardiovasc Interv. 2014;7:113-124.) 2014 American Heart
Association, Inc.
Circ Cardiovasc Interv is available at
http://circinterventions.ahajournals.org DOI:
10.1161/CIRCINTERVENTIONS.113.001150
Received December 9, 2013; accepted January 2, 2014.From the
Cardio-thoraco-vascular Department, Ferrarotto Hospital, University
of Catania, Catania, Italy (D.C.); and Department of Medicine,
Division
of Cardiology, University of Florida College of
Medicine-Jacksonville, FL (D.C., D.J.A).Correspondence to Dominick
J. Angiolillo, MD, PhD, University of Florida College of
Medicine-Jacksonville, 655 W 8th St, Jacksonville, FL 32209.
E-mail [email protected]
Management of Antiplatelet and Anticoagulant Therapy in Patients
With Atrial Fibrillation in the
Setting of Acute Coronary Syndromes or Percutaneous Coronary
Interventions
Davide Capodanno, MD, PhD; Dominick J. Angiolillo, MD, PhD
Advances in Interventional Cardiology
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114 Circ Cardiovasc Interv February 2014
Stroke/Embolic Risk in Patients With AF on Anticoagulation With
VKAs or NOACsIn patients with AF, adjusted-dose warfarin and
antiplate-let agents reduce the risk for stroke by 65% and by 20%,
respectively.17 However, oral antiplatelet agents do not perform as
well as OAC with warfarin in this context. The Atrial fibril-lation
Clopidogrel Trial with Irbesartan for prevention of Vas-cular
Events (ACTIVE-W) trial performed in patients with AF plus 1 risk
factor for stroke was stopped prematurely because of a clear
evidence of superiority of OAC compared with DAPT with aspirin and
clopidogrel, particularly in those already receiving OAC at study
entry, with no increase in bleeding complications.18 In a
meta-analysis of 6 contemporary random-ized clinical trials
published between 2002 and 2012, focus-ing on patients with AF on
warfarin therapy, the stroke rates were found to be higher in
elderly, female, subjects who were VKAs nave or those with previous
stroke or transient isch-emic attack, renal impairment, previous
aspirin use, or high CHADS
2 (cardiac failure, hypertension, age, diabetes mellitus,
stroke [doubled]) score.19 However, even in the highest risk
subgroup (previous stroke), the annualized risk of stroke with
warfarin therapy was relatively low (2.5% per year). These results
have corroborated the role of OAC with warfarin as the mainstay of
cardioembolic prevention in patients with AF. In contrast, despite
its undeniable benefits, warfarin is affected by a number of known
limitations, including bleeding complica-tions, dietary or drug
interactions, and need for international normalized ratio (INR)
monitoring and dose adjustment. These limitations may contribute to
explain why only approximately half of patients who would benefit
from OAC actually receive warfarin.20 Patients deemed unsuitable
for warfarin therapy may benefit from DAPT with aspirin and
clopidogrel, which in the ACTIVE-A trial was shown to reduce the
risk of major vascular events and stroke, compared with aspirin
alone, at the price of an increased risk of major bleeding.21
NOACs, which act by directly and selectively inhibiting key
coagulation factors such as thrombin (ie, dabigatran) or fac-tor Xa
(ie, rivaroxaban and apixaban), have recently entered the market
and clinical practice guidelines for the management of patients
with nonvalvular AF.22 NOACs hold several favor-able
characteristics, including good availability, rapid onset of
action, minimal drug/food interaction, no need for coagulation
monitoring or dose adjustment, established efficacy and low risk of
bleeding.23 In meta-analyses of warfarin-controlled tri-als, NOACs
have been shown to reduce mortality significantly by 11% to 12%,
the combination of stroke and systemic embo-lism by 18% to 23%, and
intracranial hemorrhage by 21% to 54%.2154 The annualized absolute
risks of stroke or systemic embolism in these pooled analyses have
been estimated at 2.4% to 2.8% with NOACs and 3.1% to 3.5% with
warfarin.24,25
Ischemic Risk in Patients With ACS and/or Undergoing PCI on
Antiplatelet Therapy With Aspirin and P2Y12 Receptor InhibitorsDAPT
with aspirin and a P2Y
12 receptor inhibitor is the cor-
nerstone of pharmacological ischemic prevention after an ACS or
PCI.2629 Clopidogrel, the most studied P2Y
12 recep-
tor inhibitor, was shown to reduce by 20% the incidence of
cardiovascular death, nonfatal MI, or stroke in aspirin-treated
patients with ACS from the Clopidogrel in Unstable angina to
prevent Recurrent Events (CURE) trial.30 Despite a 38% relative
increase of major bleeding at 1 year with clopidogrel in the entire
cohort, the benefit of clopidogrel treatment out-weighed the risk
of bleeding. This benefit was irrespective of patient management
(invasive or noninvasive) as well as revas-cularization strategy
(PCI or coronary artery bypass grafting). In the Clopidogrel for
the Reduction of Events During Obser-vation (CREDO) trial,
long-term (1-year) clopidogrel therapy was shown to reduce the risk
of adverse ischemic events selec-tively in patients undergoing
PCI.31 However, numerous phar-macodynamic investigations have
consistently demonstrated that individual responsiveness to
clopidogrel is not uniform in all patients and is subject to
interindividual and intraindividual variability.32 In parallel, a
growing degree of evidence under-scores that recurrence of
atherothrombotic complications, including stent thrombosis, may be
attributed to poor response to clopidogrel.32 Novel platelet
P2Y
12 inhibitors approved by
regulatory authorities in both the United States and Europe
(prasugrel, ticagrelor) have generally been shown to improve
clinical outcomes in patients with ACS when compared with
clopidogrel, particularly those undergoing PCI.33
In the Trial to Assess Improvement in Therapeutic Outcomes by
Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in
Myocardial Infarction 38 (TRITON-TIMI 38) trial, during a median
follow-up of 15 months, prasugrel reduced the combined risk of
cardiovascular mortality, MI, or stroke by 19% in patients with ACS
and scheduled PCI (9.9% versus 12.1%; P
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Capodanno and Angiolillo Triple Antithrombotic Therapy in
ACS/PCI 115
documented in large retrospective series.3942 Importantly, this
combination seems to increase the hazard of bleeding regard-less of
whether a good control of percentage of time in the therapeutic
range of warfarin is achieved.43 Two different meta- analyses have
reached similar conclusions in showing that triple antithrombotic
therapy is associated with a 2-fold increased risk of major
bleeding compared with nontriple antithrombotic regimens.44,45 The
most frequent site of seri-ous bleed in patients on triple
antithrombotic therapy is the gastrointestinal tract.46
Importantly, bleeding may impact on mortality with multiple
suggested mechanisms, including pre-mature discontinuation of
antithrombotic therapies, immuno-suppression, and platelet
activation by blood transfusion and hemodynamic compromise.47
In contrast to the striking evidence on the safety hazard with
triple therapy, data on efficacy are mixed, likely as the
reflection of differences in combinations and doses of
anti-thrombotic drugs, study design, follow-up durations, bleeding
definitions, and indications for therapy in mostly retrospec-tive
and observational series.48,49 Accordingly, the 2 above- mentioned
meta-analyses yielded conflicting results, with Zhao et al45
reporting fewer major adverse cardiovascular events and mortality
with triple therapy compared with DAPT, and Gao et al44 reporting
similar outcomes between patients on triple therapy and those on
alternative regimens. Both meta-analyses, however, demonstrated a
similar benefit of triple therapy in reducing stroke.44,45
Although there are no adequate clinical data on which to base
firm recommendations, both United States and European expert
consensus documents suggest that triple therapy should be used
depending on the balance of ischemic and bleeding risk, favoring a
combination of low-dose aspirin (plus a gas-tric acid suppressing
agent, preferably a proton pump inhibi-tor), clopidogrel as the
P2Y
12 inhibitor of choice, and OAC
with warfarin, targeting an INR between 2.0 and 2.5.48,49 The
safety of this approach, particularly regarding the importance of
keeping a low-intensity anticoagulation, has been demon-strated in
a small series.50
Novel treatment strategies aimed at reducing the risk of
bleeding by varying the combination of antithrombotic agents
administered are a matter of ongoing interest. Dropping aspirin is
one of them. Recently, the results of the open-label, mul-ticenter
What is the Optimal Antiplatelet and Anticoagulant Therapy in
Patients with Oral Anticoagulation and Coronary Stenting (WOEST)
trial have been published, in which 573 patients on oral
anticoagulants (69% for AF) and undergoing PCI were randomized to
clopidogrel alone (double therapy) or clopidogrel plus aspirin
(triple therapy).51 The trial showed a large reduction in the
primary end-point of overall TIMI bleed-ing at 12 months in
patients receiving double therapy com-pared with those receiving
triple therapy (hazard ratio, 0.36; 95% confidence interval [CI],
0.260.50; P
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116 Circ Cardiovasc Interv February 2014
concomitant clopidogrel use.6264 The only phase III AF trial
that allowed concomitant use of clopidogrel was the one of
dabigatran, although given the limited number of patients any
inference on the efficacy and safety of combination with DAPT, at
present, remains speculative.60,65
In the phase 2 Prevention of Embolic and Thrombotic Events in
Patients with Persistent AF (PETRO) study, 502 patients with AF at
high risk for thromboembolic events based on qualifying inclusion
criteria were assigned to a total of 10 treatment groups to
identify a safe dose of dabigatran etexilate for subsequent
clinical development.59 Adding to a comparator arm of patients
receiving INR-adjusted warfarin alone, 3 doses of dabigatran
etexilate (50-, 150-, and 300-mg bid) were investigated in a 33
factorial modality with no aspirin or aspirin 81- or 325-mg once
daily. With such design characteristics, the PETRO study provides
meaning-ful early insights on the safety of combining aspirin and
dabigatran. Major bleeding episodes (n=4) within 12 weeks occurred
only in patients treated with dabigatran 300-mg bid plus aspirin
(6.3% versus 0% in patients treated with dabi-gatran 300-mg bid
alone; P
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Capodanno and Angiolillo Triple Antithrombotic Therapy in
ACS/PCI 117
be personalized. Unfortunately, the hazard for ischemic and
bleeding events frequently coexists in the same patient, because
these complications share multiple risk factors. In such cases, one
should carefully weigh the risk and benefit of each drug choice,
taking into account the preference of the patient. In addition, the
length of triple therapy should be sized in propor-tion to the
bleeding risk, the clinical scenario, and tight control of INR
values should be achieved in any case.
The CHADS2 risk score is advocated by the European
guidelines as a rapid, bedside means of assessing the risk of
stroke.66 Patients with CHADS
2 2 should be prescribed
OAC indefinitely, unless contraindicated, because of higher
adjusted risk of stroke per year compared with those with CHADS
2 scores of 0 or 1, for whom DAPT is preferable.67
However, these latter continue to experience a certain degree of
stroke risk, which underscores the need for more precise assessment
of stroke risk factors in this population. An updated scheme
expressed as CHA
2DS
2-VASc (conges-
tive heart failure, hypertension, age 75 [doubled], diabe-tes
mellitus, stroke [doubled], vascular disease, age 6574, and sex
category [female]) has been proposed to fulfill this aim by
incorporating additional stroke risk factors that influ-ence
whether or not to use OAC into the simpler CHADS
2
scheme.66 With such approach, OAC should be prescribed only in
patients with CHA
2DS
2-VASc 2, whereas those with
a score of 1 should be prescribed either OAC (preferred) or
aspirin, and those with a score of 0 should be prescribed no
antithrombotic therapy for AF (preferred) or aspirin alone.
Similarly, risk stratification tools are available to estimate
the individual risk of bleeding.68 The European guidelines
for-mally endorse the HAS-BLED (hypertension, abnormal renal/liver
function, stroke, bleeding history or predisposition, labile INR,
elderly [>65], drugs/alcohol concomitantly) as a simple method
to assess bleeding risk in patients with AF, with scores 3
indicating high risk. The HAS-BLED score has been found to predict
bleeding significantly also in patients on triple anti-thrombotic
therapy, with a relatively good discrimination (c statistic,
0.67).69 In a study of 590 patients with AF and CHA
2DS
2-VASc 1 undergoing PCI, 71% had a HAS-BLED
3.70 In these patients, OAC was found to reduce the risk of
death at 12 month independently, whereas the use of DES, with
subsequent need for prolonged DAPT, independently predicted the
risk of major bleeding. Interestingly, similar results have been
demonstrated in octagenarian patients with AF undergoing PCI (mean
HAS-BLED, 3.05).71 Overall, these findings underscore that the
benefit of using VKAs on top of DAPT to reduce ischemic events may
overshadow the bleed-ing risk even in patients with HAS-BLED 3.
This is also in line with registry data showing that patients with
AF undergo-ing PCI have a CHADS
2 score 2 in 70% of cases, so that
OAC treatment should not be withdrawn even when combined
anticoagulant and antiplatelet treatment is warranted.72
Procedural Considerations for Minimizing the Risk of Bleeding
With Triple Antithrombotic TherapyA series of procedural aspects
need to be taken into consider-ation when dealing with a patient in
need of triple antithrom-botic therapy. Given the complexity and
risk associated with management of these patients, it is first
important to define
whether there is an indication to be on triple antiplatelet
ther-apy. In fact, there are subgroups of patients with AF with a
low annual risk of thromboembolic events (ie, CHA
2DS
2-VASc 0
or 1) that do not require OAC. Also, the reduction in stroke
with well-controlled warfarin therapy versus DAPT in patients at
lower risk of stroke is likely outweighed by the increased risk of
bleeding.18 It is also important to note that compliance with
treatment is pivotal for demonstrating efficacy with OAC and to
minimize bleeding complications. In fact, patients with a time in
the therapeutic range
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118 Circ Cardiovasc Interv February 2014
where the safety gain is paralleled by the superior efficacy of
DES in reducing the need for repeat revascularization.8183
On this background, the benefit of a DES over a BMS should be
balanced against the increased risk of bleeding with a prolonged
triple therapy. The optimal duration of DAPT after DES implantation
is still a controversial issue, with large ongoing trials
(clinicaltrials.gov identifiers NCT00977938 and NCT00661206) aimed
at shedding more light on this topic.84 As noted above,
second-generation devices, including stents eluting everolimus or
zotarolimus, might offer ideal fea-tures such as less
thrombogenicity and no need for long-term DAPT.78,79 The Xience and
Promus everolimus-eluting stents have recently gained European CE
Mark approval for use with DAPT for 3 months, and the Resolute
Integrity zotarolimus- eluting stent for 1 month.85,86 These data
have been supported by studies and presentations at major
cardiovascular con-gresses demonstrating that discontinuation of
DAPT after either 1, 3, or 6 months duration was not associated
with a sig-nificant increase in stent thrombosis with these newer
stents among low-risk all-comers populations.8791 This is also in
line with a recent large registry supporting the relative safety of
DES versus BMS should DAPT discontinuation be required early (ie,
between 6 weeks and 6 months).92
Overall, the net clinical benefit of treatment with BMS and OAC
in conjunction with either mono (clopidogrel) or dual (aspirin plus
clopidogrel) antiplatelet therapy remains to be determined when
compared with treatment using a second- generation DES
(specifically Xience/Promus and/or Resolute Integrity) in
conjunction with an abbreviated (13 months) duration of DAPT, but
could clearly weigh in favor of the newer generation DES in
conjunction with an abbreviated DAPT reg-imen. Bioresorbable
coronary scaffolds may have the potential for reducing late
thrombotic events in patients undergoing PCI, but the scaffold
persists 1 to 2 years, and large-scale studies are needed to
characterize the safety of this new technology.93
Intraprocedural AnticoagulationManagement of anticoagulant
therapy during PCI is mostly empirical in patients on OAC because
of lack of a solid evi-dence base. In the multicenter Atrial
Fibrillation undergoing Coronary Artery Stenting (AFCAS) registry,
uninterrupted anticoagulation was shown to be similar to
conventional bridging therapy with heparin, after adjustment for
propensity score, in terms of both major adverse cardiac and
cerebrovas-cular events (1.16; 95% CI, 0.443.05; P=0.76) and
bleeding complications (1.38; 95% CI, 0.772.48; P=0.28).94 However,
whether continuation of OAC is a safe option in the peri-PCI period
remains unproven without confirmation from a dedi-cated randomized
clinical trial.
Current US guidelines consider enoxaparin a reasonable option in
patients either treated with upstream subcutaneous enoxaparin in
the context of an NSTE-ACS (to whom addi-tional dose of 0.3 mg/kg
IV should be administered at the time of PCI to patients who have
received
-
Capodanno and Angiolillo Triple Antithrombotic Therapy in
ACS/PCI 119
undergoing PCI with stenting provides recommendations based on
the individual risk for stent thrombosis (ie, low, high, any) and
the risk of bleeding (ie, low, high).49 Patients at low risk of
both stent thrombosis and bleeding should receive triple therapy
for 1 month after placement of a BMS and for 6 months after
placement of a DES, followed by OAC plus 1 antiplatelet agent (ie,
aspirin or clopidogrel) up to 12 months, with OAC only continued
thereafter. In contrast, patients at high risk of stent thrombosis
and low risk of bleeding should receive triple therapy for 6 months
after a BMS, and for 12 months after a DES. After 12 months,
continuation of a single antiplatelet agent in addition to OAC
should be considered in patients at high risk for stent thrombosis.
Finally, regard-less of the risk of stent thrombosis, patients at
high bleeding risk should receive a BMS and maintain triple therapy
for 1 month, followed by OAC plus 1 antiplatelet agent up to 12
months and OAC indefinitely thereafter.
The parallel European expert consensus document pro-vides
recommendations following a different approach that take into
consideration bleeding on one hand, and clini-cal presentation on
the other.48 In elective PCI patients who receive BMS and are at
low or intermediate risk of bleeding (HAS-BLED 2.0.
Use of Proton Pump InhibitorsAccording to an expert consensus
document and the Ameri-can College of Cardiology/the American Heart
Association PCI guidelines, use of proton pump inhibitors should be
encouraged in patients on DAPT therapy to reduce the risk of
gastrointestinal bleeding, particularly in case of concurrent use
of OAC.29,106 However, pharmacokinetic and pharmaco-dynamic studies
suggest that concomitant use of clopidogrel and omeprazole reduces
the antiplatelet effects of clopidogrel, possibly through
competitive metabolic effects of cytochrome CYP2C19 or reduced
biological action of clopidogrel related to genetic polymorphisms,
leading to a box warning from drug regulating agencies in the
United States and Europe.107 Although retrospective studies and
post hoc analysis have suggested a potential for an increased risk
of ischemic events attributable to this drugdrug interaction,108
this has not proven to translate into meaningful differences at the
clinical level in a randomized clinical trial.109 It should be
noted that the inter-action of clopidogrel with proton pump
inhibitors is not class specific because it applies to only those
drugs (ie, omeprazole and esomeprazole) interfering with the
CYP2C19.110,111 There-fore, in line with PCI guidelines,
non-CYP2C19 interfering proton pump inhibitors (ie, pantoprazole,
dexlansoprazole) should be preferred.29
Managing Bleeding ComplicationsIn case of bleeding or in
asymptomatic patients with exces-sively high INR values, strategies
aimed at reversing the effect of oral antithrombotic drugs may be
necessary. Antagonizing the effect of warfarin requires suspending
the drug and eventu-ally administering a dose of vitamin K
(phytonadione) or blood derivatives, including fresh frozen plasma
or prothrombin complex concentrates. There are currently no
specific antidotes to neutralize the effect of NOACs, although
several different drugs and compounds are under investigation as
potential reversing agents.101 Clopidogrel, prasugrel, and
ticagrelor have no antidotes. When an antidote is not available and
bleeding continues despite the usual hemostatic techniques,
platelet transfusion has the potential to reverse bleeding by
restoring normal hemostasis, even if platelet count is normal, at
the price of a slightly increased risk of platelet activation and
aggrega-tion.112,113 If deemed necessary in patients treated with
novel P2Y
12 inhibitors, platelets should be administered 6 hours
after administration of the loading dose of prasugrel or 4 hours
after the administration of the maintenance dose, to avoid
interference by the circulating active metabolite of the drug.114
No data exist on the hemostatic benefit of platelet transfusion in
patients treated with ticagrelor.
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120 Circ Cardiovasc Interv February 2014
Future DirectionsTwo randomized clinical trials are currently
testing different antithrombotic combinations for patients on OAC
who require stent implantation. The Triple Therapy in Patients on
Oral Anticoagulation After Drug Eluting Stent Implantation
(ISAR-TRIPLE, clinicaltrials.gov id NCT00776633) trial will address
the hypothesis that reducing the length of clopidogrel therapy from
6 months to 6 weeks after implantation of DES is associ-ated with a
reduced net composite of death, MI, definite stent thrombosis,
stroke, or major bleeding at 9 months on top of treatment with
aspirin and an oral anticoagulant. The Antico-agulation in Stent
Intervention (MUSICA-2, clinicaltrials.gov id NCT01141153) trial is
investigating the safety and efficacy of a triple antithrombotic
regimen of acenocoumarol, low-dose (100 mg/d) aspirin, and
clopidogrel versus high-dose (300 mg/d) aspirin and clopidogrel in
patients with AF and low-to-moderate risk of stroke (CHADS
2 2) referred to PCI.
After an ACS, patients remain at risk for recurrent
athero-thrombotic events despite the use of DAPT.34,37 This risk
may be partly related to excess thrombin generation, supporting the
rationale for use of an anticoagulant on top of DAPT at long-term
after an ACS. This strategy was shown to be of potential use with
warfarin (but challenges related with drug administration and
bleeding concerns have limited its use for this indication) and
ximelagatran (but the drug is no longer on the market because of
reported hepatotoxicity).115,116 The advent of NOACs has renewed
the interest toward the long-term use of oral anticoagulants in
ACS. However, dabigatran and dar-exaban were associated with a
dose-dependent increased risk of bleeding in their respective phase
II trials,117,118 and apixa-ban increased the number of major
bleeding events without a significant reduction in the rate of
ischemic events in a phase III trial.119 Another phase III trial of
low-dose rivaroxaban (2.5-mg bid) on top of aspirin and clopidogrel
in patients with ACS showed a significant reduction in mortality at
the price of a 4-fold increase in intracranial hemorrhage.120
Importantly, the 2.5-mg bid dose of rivaroxaban used in the trial
was about one quarter of that tested in AF. Therefore, whether this
regi-men would be sufficiently safe and protective in AF versus
warfarin or the combination of a higher dose of rivaroxaban plus a
P2Y
12 inhibitor only is unknown and will be assessed
in a 2100-patient prospective trial (A Study Exploring Two
Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in
Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary
Intervention [PIONEER AF-PCI], clinicaltrials.gov identifier
NCT01830543). In this trial, patients with nonvalvular AF
undergoing PCI with no history of previous transient ischemic
attack or stroke will be random-ized to 1 of 3 treatment arms: (1)
triple antithrombotic therapy with aspirin (75100 mg/d),
clopidogrel (75 mg/d), and VKAs (INR, 2.03.0); at the discretion of
the treating physician, patients will drop clopidogrel at 1, 6, or
12 months, which will be defined at time of randomization; (2)
triple antithrombotic therapy with aspirin (75100 mg/d),
clopidogrel (75 mg/d), and rivaroxaban (2.5-mg bid); at the
discretion of the treating physician, patients will drop
clopidogrel at 1, 6, or 12 months, which will be defined at time of
randomization; (3) dual anti-thrombotic therapy with rivaroxaban
15-mg/d (or 10-mg for subjects with moderate renal impairment) and
clopidogrel (75
mg/d). In a small subgroup of patients, the novel P2Y12
recep-tor antagonists, prasugrel (10 mg/d), or ticagrelor (90 mg
bid), will be allowed to be used in lieu of clopidogrel. The
primary end-point will be the 12-month composite of TIMI major
bleeding, TIMI minor bleeding, and bleeding requiring medi-cal
attention. The secondary end-point will be the composite of
cardiovascular death, MI, stroke, and stent thrombosis. Most
recently, a trial of dabigatran 150-mg or 110-mg twice-daily plus
single antiplatelet therapy versus triple therapy with war-farin
and DAPT (Randomized Evaluation of Dual Therapy with Dabigatran
versus Triple Therapy Strategy with Warfarin in Patients with
nonvalvular atrial fibrillation that have undergone PCI with
Stenting [RE-DUAL PCI]) has been announced.121
ConclusionsTriple therapy with OAC, aspirin, and clopidogrel is
recom-mended for patients with AF with ACS and/or PCI, but
evi-dence mainly stems from observational series, mostly from
single centers. For this reason, European and US guidelines assign
a C level of evidence to this recommendation, and emphasize the
need for balancing the thrombotic and the bleeding risks at the
individual level. Incorporation of NOACs, prasugrel, and ticagrelor
into a triple therapy scheme is chal-lenging in a field where data
are limited. Further investigation of less-is-more approaches (ie,
WOEST-like trials) is crucial to confirm the effectiveness of
adding 2 and not 1 antiplatelet agent on top of OAC.
DisclosuresDr Capodanno received payment as an individual for
consulting fee or honorarium from Eli-Lilly, Daiichi Sankyo,
AstraZeneca, and The Medicines Company. Dr Angiolillo received
payment as an in-dividual for the following: (1) Consulting fee or
honorarium from Bristol Myers Squibb, Sanofi-Aventis, Eli-Lilly,
Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva,
Abbott Vascular and PLx Pharma; (2) Participation in review
activities from Johnson & Johnson, St Jude, and Sunovion.
Institutional payments for grants from Bristol Myers Squibb,
Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli-Lilly, Daiichi Sankyo,
The Medicines Company, AstraZeneca, Evolva, Gilead; and has other
financial relationships with Esther and King Biomedical Research
Grant.
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Davide Capodanno and Dominick J. AngiolilloInterventions
Fibrillation in the Setting of Acute Coronary Syndromes or
Percutaneous Coronary Management of Antiplatelet and Anticoagulant
Therapy in Patients With Atrial
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Interventions
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