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Duration of Triple Antithrombotic Therapy and Outcomes Among Patients Undergoing Percutaneous Coronary Intervention
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 9, NO. 14, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2016.04.027
Duration of Triple Antithrombotic Therapy and Outcomes Among Patients Undergoing Percutaneous Coronary Intervention Konstantinos C. Koskinas, MD, MSC,a Lorenz Räber, MD, PHD,a Thomas Zanchin, MD,a Thomas Pilgrim, MD,a Stefan Stortecky, MD,a Lukas Hunziker, MD,a Stefan Blöchlinger, MD,a Michael Billinger, MD,a Fabienne Gartwyl, BA,a Christina Moro, MA,a Aris Moschovitis, MD,a Peter Jüni, MD,b Dik Heg, PHD,c Stephan Windecker, MDa
ABSTRACT OBJECTIVES The aim of this study was to compare clinical outcomes in relation to the duration of triple antithrombotic therapy (TAT) among patients with indications for oral anticoagulation undergoing percutaneous coronary intervention (PCI). BACKGROUND TAT is recommended for patients undergoing PCI with a firm indication for oral anticoagulation. Duration of TAT may influence outcomes, but the optimal period of TAT remains uncertain. METHODS Between 2009 and 2013, 8,772 consecutive patients undergoing PCI for stable coronary artery disease or acute coronary syndrome were prospectively included in the Bern PCI Registry (NCT02241291). Of 568 patients with indications for oral anticoagulation, 245 (43%) were discharged on a regimen of 1-month TAT and 323 (57%) on a regimen >1-month TAT (mean 5.1 3.3 months, median 3 months). The primary endpoint was a composite of cardiac death, myocardial infarction, stroke, definite stent thrombosis, or TIMI (Thrombolysis in Myocardial Infarction) major bleeding within 1 year. RESULTS Patients on 1-month compared with >1-month TAT were more commonly women, with stable coronary artery disease, had higher HAS-BLED scores, and less frequently received drug-eluting stents. In multivariate analyses, the primary endpoint did not differ between groups (adjusted hazard ratio: 1.07; 95% confidence interval: 0.56 to 2.06; p ¼ 0.84). Results were consistent in stratified analyses in relation to clinical presentation with acute coronary syndrome (38%) and PCI with drug-eluting stents (79%) (p for interaction ¼ 0.18 and 0.95, respectively). There were no differences in the secondary bleeding endpoint, Bleeding Academic Research Consortium $3 bleeding (adjusted hazard ratio: 0.62; 95% confidence interval: 0.21 to 1.80; p ¼ 0.37) and the secondary composite ischemic endpoint (cardiac death, myocardial infarction, stroke, or definite stent thrombosis) (adjusted hazard ratio: 1.12; 95% confidence interval: 0.55 to 2.29; p ¼ 0.76). CONCLUSIONS One-month TAT, used preferentially in patients with higher estimated bleeding risk in this observational study, was associated with similar net clinical outcomes compared with longer TAT durations throughout 1 year following PCI. (J Am Coll Cardiol Intv 2016;9:1473–83) © 2016 by the American College of Cardiology Foundation.
From the aDepartment of Cardiology, Bern University Hospital, Bern, Switzerland; bDepartment of Medicine, University of Toronto, Toronto, Canada; and the cInstitute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. Dr. Jüni is an unpaid steering committee or statistical executive committee member of trials funded by Abbott Vascular, Biosensors, Medtronic, and St. Jude Medical. Prof. Windecker has received research contracts to the institution from Abbott Vascular, AstraZeneca, Boston Scientific, Biosensors, Biotronik, Cordis, Eli Lilly, Medtronic, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Koskinas and Räber contributed equally to this work. Manuscript received February 3, 2016; revised manuscript received March 30, 2016, accepted April 21, 2016.
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Duration of Triple Therapy and PCI Outcomes
U
ABBREVIATIONS AND ACRONYMS
p to 10% of patients undergoing
METHODS
percutaneous coronary intervention (PCI) have concomitant indica-
PATIENT POPULATION. This was a retrospective
tions for oral anticoagulation (OAC) (1,2). The
analysis of prospectively collected data. All consecu-
therapeutic targets of OAC protecting against
tive patients undergoing PCI for stable coronary artery
ischemic complications related to fibrin-rich
disease (CAD) or acute coronary syndrome (ACS)
thrombus in patients with atrial fibrillation
at Bern University Hospital (Bern, Switzerland) as
(AF) or mechanical valves (3,4) versus dual-
of 2009 were prospectively entered into the Bern
antiplatelet therapy (DAPT) for prevention
PCI Registry (NCT02241291). The present analysis
of platelet-dependent stent thrombosis (5,6)
included all consecutive patients with clinical in-
are
on
dications for OAC who were discharged on TAT. Per
different pathobiological pathways. There-
default, most patients requiring OAC at our institution
fore, a combination of OAC plus DAPT is
receive
plausible among patients with indications for
following PCI instead of less intensive antithrombotic
OAC = oral anticoagulation
OAC undergoing PCI and is currently recom-
regimens (e.g., OAC plus antiplatelet monotherapy).
PCI = percutaneous coronary
mended in consensus documents (1,7–9).
In line with the inclusive character of the registry,
Triple antithrombotic therapy (TAT), the
there were no formal exclusion criteria. Demographic
combination of OAC and DAPT, is associated
and clinical characteristics, information on performed
with increased bleeding risk (10,11) but is
interventions, and hospital outcome data were sys-
more effective than DAPT alone for reduction of
tematically collected. Scores of HAS-BLED (hyper-
major adverse cardiovascular events in these patients
tension, abnormal liver or renal function, stroke or
(1,12,13).
thromboembolism, bleeding history, elderly [age >65
ACS = acute coronary syndrome(s)
AF = atrial fibrillation BMS = bare-metal stent(s) CAD = coronary artery disease CI = confidence interval DAPT = dual-antiplatelet therapy
DES = drug-eluting stent(s) HR = hazard ratio MI = myocardial infarction
intervention
TAT = triple antithrombotic therapy
complementary
and
dependent
intensive
antithrombotic
DAPT
of
differing
duration
years], drug consumption or alcohol abuse) were
SEE PAGE 1484
Less
additional
calculated, excluding labile international normalized regimens
(e.g.,
ratio values, which were not collected. The registry
omission of aspirin) have received attention as a po-
was approved by the institutional ethics committee,
tential means of mitigating bleeding risk (14–16) and
and patients provided written informed consent to
may be considered as an alternative to TAT in selected
undergo prospective follow-up.
patients (1,7,8). Abbreviated regimens of TAT may be explored as an alternative strategy to optimize the benefit-to-risk ratio in view of the fact that bleeding associated with TAT appears to be exposure dependent and related to treatment duration (17). In this context, the ISAR-TRIPLE (Intracoronary Stenting and Antithrombotic Regimen–Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment Regimen in Patients With Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting) randomized trial reported comparable net clinical outcomes with 6-week versus 6-month TAT following PCI with drugeluting stent (DES), supporting the role of shorter TAT duration in this setting (18). The length of TAT is currently recommended to be adjusted according to individual thrombotic and bleeding risk, clinical presentation, and type of stent; these recommendations remain largely consensus rather than evidence based, as reflected by the low level of evidence and differences
PROCEDURES. PCI was performed in accordance with
current practice guidelines (7). Periprocedural management, including interrupted versus uninterrupted OAC, dose of unfractionated heparin, or use of glycoprotein IIb/IIIa inhibitors, was left to the discretion of the operator. DAPT consisting of acetylsalicylic acid and a P2Y12 inhibitor was initiated before, at the time of, or immediately after the procedure. The P2Y 12 inhibitor of choice was clopidogrel in the majority of patients. Ticagrelor or prasugrel was administered if deemed clinically necessary by the treating physician in certain cases of ACS, complex anatomy, or complicated interventions; prasugrel was selectively used before the excessive bleeding risk for TAT including prasugrel was reported (20). The duration of DAPT was not uniformly specified but individualized accounting for each patient’s clinical presentation, ischemic and bleeding risk profile.
between European (1,7,8) and North American guide-
PATIENT FOLLOW-UP. Patients were systematically
lines regarding specific TAT durations (19).
followed at discharge and throughout 1 year to assess
Against this background, the purpose of the pres-
adverse cardiac and cerebrovascular events. Survival
ent observational study was to compare clinical out-
data were obtained from hospital records and
comes in relation to a regimen of 1-month versus
municipal civil registries. A health questionnaire was
more prolonged TAT in a cohort of unselected pa-
sent to all living patients with questions on rehospi-
tients undergoing PCI with indications for OAC.
talization, medical treatment, and adverse events,
Koskinas et al.
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Duration of Triple Therapy and PCI Outcomes
followed by telephone contact in case of missing response. General practitioners, referring cardiolo-
F I G U R E 1 Frequency Distribution of Triple-Antithrombotic Therapy Durations
gists, and patients were contacted, and external medical records, discharge letters, and coronary angiography
documentation
were
systematically
reviewed as necessary for additional information. Medical treatment was recorded during index PCI, at discharge, and at 1 year. CLINICAL ENDPOINTS AND STUDY ASSESSMENTS.
A clinical event committee consisting of 2 cardiologists (and in case of disagreement of a third referee) adjudicated all events using original source documents. Cardiac death was defined as any death due to an immediate cardiac cause, procedure-related mortality, and death of unknown cause. Stent thrombosis and myocardial infarction (MI) were defined according to the Academic Research Consortium criteria (21) and the modified historical definition (22), respectively. Stroke was defined as rapid development of clinical signs of focal or global disturbance of cerebral function lasting >24 h with imaging evidence of acute, clinically relevant brain lesion. Bleeding events were categorized according to the Bleeding Academic Research Consortium (BARC) and TIMI (Thrombolysis In Myocardial Infarction) classifications (23). For this analysis, patients were categorized into those discharged with 1-month versus more prolonged (>1 month) TAT following PCI. Categorization was based on prescription times at discharge and
One-month triple antithrombotic therapy (TAT) was prescribed to 43% of all patients (A,B) but 76% of patients with HAS-BLED scores $3 (C).
not actual duration of treatment. The primary endpoint was a composite of cardiac death, MI,
College Station, Texas). Continuous variables are
stroke, definite stent thrombosis, or TIMI major
summarized as mean SD or median (interquartile
bleeding. The rationale for a combined ischemic and
range) and categorical variables as actual numbers and
bleeding endpoint is in line with the primary assess-
percentages. Baseline and procedural characteristics
ment of the ISAR-TRIPLE trial (18) (currently the only
and medications were compared using Fisher exact
randomized trial comparing different TAT durations
tests for binary responses, chi-square tests for more
post-PCI),
recognizing
that
both
ischemic
and
than 2 responses, unpaired Student t tests for means,
bleeding complications adversely affect prognosis
and Mann-Whitney U tests for medians. Clinical out-
following PCI (24). The secondary bleeding endpoint
comes were analyzed using Cox regression analysis
was BARC $3 bleeding; the secondary ischemic
(time to first event). All adjusted models were based on
endpoint was the composite of cardiac death, MI,
20 datasets created using chained equations to impute
stroke, or definite stent thrombosis.
missing date (estimates combined using Rubin’s rule).
The main analysis compared outcomes within
Subsequently, adjustment was made for the following
12 months in relation to prescribed TAT duration.
baseline covariates: sex, clinical presentation with
Exploratory analyses included: 1) landmark analyses
ACS, HAS-BLED score, use of any DES, and multiple-
set at 30 days (i.e., focusing on the period after
lesion treatment. Findings were considered statisti-
expected TAT cessation in the short-duration group);
cally significant at the 0.05 level.
2)
sensitivity
analyses
excluding
patients
with
ST-segment elevation MI as well as those receiving prasugrel or ticagrelor; and 3) stratified analyses in relation to stent type and clinical presentation.
RESULTS Between March 2009 and December 2013, 8,772
STATISTICAL ANALYSES. Statistical analyses were
consecutive patients undergoing PCI were included in
performed with Stata version 14.0 (StataCorp LP,
the Bern PCI Registry. Of 568 patients with clinical
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Duration of Triple Therapy and PCI Outcomes
(n ¼ 448 [79%]) received new-generation DES.
T A B L E 1 Baseline Characteristics of the Study Population
Age, yrs
Patients with 1-month TAT were more commonly
TAT 1 Month (n ¼ 245)
TAT >1 Month (n ¼ 323)
73.4 8.9
72.5 10.0
p Value
0.261
treated with bare-metal stents (BMS) or balloon angioplasty without stents. Medication use during index procedure, at discharge, and at 1-year follow-up
Male
179 (73.1)
259 (80.2)
0.055
Body mass index, kg/m2
28.2 5.5
28.0 5.2
0.64
Diabetes mellitus
63 (25.8)
107 (33.2)
0.06
glycoprotein IIb/IIIa inhibitors during the index pro-
Hypertension
190 (78.5)
254 (79.4)
0.83
cedure, more commonly received clopidogrel, and
Dyslipidemia
168 (69.1)
206 (64.4)
0.24
less frequently received prasugrel at discharge.
Current smoker
30 (12.4)
51 (16.2)
0.23
is summarized in Table 3. Patients with 1-month versus longer term TAT less frequently received
Cardiovascular risk factors
Renal dysfunction
86/222 (38.7)
94/281 (33.5)
0.22
CLINICAL OUTCOMES IN RELATION TO TAT DURATION.
Anemia
62/214 (29.0)
96/286 (33.6)
0.29
Clinical outcomes within 30 days are summarized in
Thrombocytopenia
30/214 (14.0)
32/281 (11.4)
0.41
Online Table 1. At 12 months, complete follow-up was
Previous MI
56 (22.9)
75 (23.2)
1.00
available in 533 patients (93.8%) (Online Table 2). At
Previous PCI
75 (30.7)
89 (27.6)
0.45
Previous CABG
47 (19.2)
62 (19.2)
1.00
Clinical presentation Stable CAD Unstable angina NSTEMI STEMI
0.001
Pulmonary embolism Mechanical valve
in 22 patients (9.5%) discharged on 1-month TAT and
171 (69.8)
182 (56.3)
0.001
in 39 patients (12.9%) with longer TAT (hazard ratio
14 (5.7)
15 (4.6)
0.57
[HR]: 0.72; 95% confidence interval [CI]: 0.42 to 1.21;
46 (18.8)
80 (24.8)
0.10
p ¼ 0.21) (Table 4). Differences were not significant in
14 (5.7)
46 (14.2)
0.001
multivariate analysis (adjusted HR: 1.07; 95% CI: 0.56
138 (56.3)
177 (55.3)
0.86
29 (11.8)
28 (8.8)
0.26
8 (3.3)
17 (5.3)
0.30
Indication for OAC Atrial fibrillation
1 year, the primary composite endpoint had occurred
to 2.06; p ¼ 0.84) (Figure 2A) as well as in a landmark analysis between 1 and 12 months (adjusted HR: 0.89; 95% CI: 0.48 to 1.66; p ¼ 0.72) (Figure 2B). Rates of the
Deep venous thrombosis
14 (5.7)
20 (6.3)
0.86
secondary bleeding endpoint, BARC $3 bleeding
LVEF <30% or LV thrombus
28 (11.4)
38 (11.9)
0.89
(adjusted HR: 0.62; 95% CI: 0.21 to 1.80; p ¼ 0.37) or
9 (3.7)
16 (5.0)
0.54
TIMI major bleeding, were similar, also in landmark
HAS-BLED score
2.8 0.9
1.9 0.7
<0.001
analyses set at 1 month (Figure 3). We found no sig-
HAS-BLED score $3
138 (56.3)
43 (13.3)
<0.001
nificant differences regarding the combined ischemic
Miscellaneous
Values are mean SD or count (%). The p values are from Fisher exact tests (2 categories), chi-square tests (clinical presentation), and unpaired Student t tests (age, body mass index, and HAS-BLED score). CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; OAC ¼ oral anticoagulation; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction; TAT ¼ triple antithrombotic therapy.
endpoint (adjusted HR: 1.12; 95% CI: 0.55 to 2.29; p ¼ 0.76) (Figure 4) or its individual components (cardiac death, MI, stroke, or definite stent thrombosis) (Table 4). Results were consistent in sensitivity analyses excluding patients who were discharged with prasugrel or ticagrelor as part of TAT (n ¼ 15; 1 in the 1-month TAT group and 14 in the >1-month TAT group) (Online Table 3), as well as after the exclusion
indications for OAC who received TAT, 245 (43.1%)
of patients with ST-segment elevation MI (i.e.,
were discharged on TAT for 1 month and 323 (56.9%)
patients at presumed highest thrombotic risk) (Online
for >1 month (median 3 months; interquartile range: 3
Table 4). The primary endpoint did not differ significantly
to 6 months) (Figure 1). BASELINE CHARACTERISTICS. Baseline characteris-
tics are summarized in Table 1. The most common indication for OAC was AF (55%). Patients discharged with
1-month
versus
longer
TAT
were
more
commonly women, presented more often with stable CAD, had higher HAS-BLED scores (2.8 0.9 vs. 1.9 0.7; p < 0.001), and more frequently had HAS-BLED scores $3 (56.3% vs. 13.3%; p < 0.001).
in relation to TAT duration in exploratory analyses stratified for stable CAD versus ACS (p for interaction ¼ 0.18), PCI with or without DES (p for interaction ¼ 0.95), and AF as the primary indication for OAC (p for interaction ¼ 0.55) (Figure 5). Similarly, no difference was observed in stratified analyses for the secondary ischemic and bleeding endpoints (Figure 5) and for TIMI major bleeding (Online Figure 1).
Short (1-month) TAT duration was prescribed in 76.2% of patients with HAS-BLED scores $3 and in 27.6% of
DISCUSSION
patients with HAS-BLED scores #2 (Figure 1C). Procedural characteristics during the index inter-
Although TAT is currently recommended for patients
vention are shown in Table 2. The majority of patients
with indications for OAC who undergo PCI, optimal
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Duration of Triple Therapy and PCI Outcomes
T A B L E 2 Procedural Characteristics
T A B L E 3 Medications During Percutaneous Coronary Intervention, at
Discharge, and at 1 Year
TAT 1 Month (n ¼ 245)
TAT >1 Month (n ¼ 323)
383
554
Number of lesions per patient
1.6 0.9
1.7 0.9
0.16
Multiple-lesion treatment
98 (40.0)
152 (47.1)
0.10
Number of lesions
Balloon angioplasty
0.016 522 (94.4)
39 (10.2)
31 (5.6)
207 (60.2)
503 (96.4)
<0.001
3 (0.9)
69 (13.2)
<0.001
Everolimus eluting
112 (32.6)
245 (46.9)
0.002
BP sirolimus eluting
61 (17.7)
104 (19.9)
0.57
Mean stent diameter, mm per lesion
Abciximab
Clopidogrel
Biolimus eluting
Total stent length, mm per lesion
Glycoprotein IIb/IIIa inhibitors
None
New-generation DES
Zotarolimus eluting
TAT >1 Month (n ¼ 323)
238 (97.1)
313 (97.8)
4 (1.6)
15 (4.7)
0.06
4 (1.6)
14 (4.4)
0.09
12 (5.0)
25 (7.9)
0.17
Loading dose 344 (89.8)
Stent type per lesion*
Bare metal
TAT 1 Month (n ¼ 245)
33 (9.6)
85 (16.3)
0.035
137 (39.8)
19 (3.6)
<0.001
3.0 0.5
2.9 0.5
0.012
22.4 14.0
24.6 14.0
0.033
Values are mean SD or count (%). The p values are from Poisson regression (number of lesions), Fisher exact test (multiple-lesion treatment), or otherwise cluster-robust general or generalized linear models accounting for lesions nested within patients. *Mixing stents of different types inside the same lesion explains double counting. BP ¼ biodegradable polymer; DES ¼ drug-eluting stent(s); TAT ¼ triple antithrombotic therapy.
0.79
0.28 216 (89.3)
265 (83.9)
0.08
Prasugrel
4 (1.7)
11 (3.5)
0.29
Ticagrelor
10 (4.1)
12 (3.8)
0.83
Clopidogrel and prasugrel
0 (0.0)
2 (0.6)
0.51
Clopidogrel and ticagrelor
0 (0.0)
1 (0.3)
1.00
At discharge Acetylsalicylic acid
245 (100.0)
323 (100)
Clopidogrel
244 (99.5)
311 (96.3)
0.03
7 (2.2)
0.02
7 (2.2)
0.15
Prasugrel Ticagrelor
0 (0.0) 1 (0.4)
Any dual-antiplatelet therapy
245 (100)
323 (100.0)
Oral anticoagulation
245 (100)
323 (100)
232 (94.7)
317 (98.1)
0.04
13 (5.3)
6 (1.9)
0.03
Vitamin K antagonist Novel oral anticoagulation At 1 yr Acetylsalicylic acid
167/209 (79.9)
218/264 (82.6)
0.48
55/209 (26.3)
91/264 (34.5)
0.06
Prasugrel
3/209 (1.4)
4/264 (1.5)
1.00
Ticagrelor
0/209 (0.0)
1/264 (0.4)
1.00
45/209 (21.5)
62/261 (23.5)
0.66
167/208 (80.3)
205/261 (78.6)
157/208 (75.5)
192/261 (73.6)
0.67
10/208 (4.8)
13/261 (5.0)
1.00
Clopidogrel
Any dual-antiplatelet therapy
duration of TAT treatment is not well established (1).
p Value
During PCI Unfractionated heparin
Type of intervention per lesion Stenting
p Value
Oral anticoagulation
The main finding of this observational study is that an
Vitamin K antagonist
abbreviated, 1-month duration of TAT, determined by
Novel oral anticoagulation
treating physicians according to individual patient risk profiles, was associated with similar bleeding and ischemic complications and net clinical outcomes
Values are count (%). The p values are from Fisher exact tests (2 categories) or chi-square test (loading dose). TAT ¼ triple antithrombotic therapy.
throughout 1 year compared with more prolonged TAT regimens. Notwithstanding inherent limitations of nonrandomized investigations, these findings add
advocate patient-tailored reduction of TAT duration
to evidence indicating that shorter, patient-tailored
and specifically to 1 month in patients at high
DAPT durations assume a role in the management of
bleeding risk (e.g., HAS-BLED score $3) or presenting
orally anticoagulated patients undergoing coronary
with stable CAD (1,7,8). Our finding of similar net
interventions (18). They also support current, largely
clinical outcomes with short (1-month) compared
consensus-based recommendations regarding the
with longer TAT adds new evidence in support of
length of TAT treatment in this specific clinical
expert consensus statements and consistent guide-
setting (1,7–9,19).
lines (1,7–9,19). These results held true after multi-
In patients who require OAC and receive coronary
variate adjustments including clinical presentation
stents, balancing the ischemic versus bleeding hazard
and stent type as well as in sensitivity analyses
remains a challenging task. Long-term TAT increases
focusing on patients with ACS, those with AF as
the risk for bleeding, including major and fatal
an indication for OAC, and those treated with DES
bleeding (14–16,25), but may be more effective and in
(i.e., more than one-half of patients in the 1-month
selected studies appeared to improve patient out-
and >90% of patients in the longer term TAT
comes compared with DAPT alone (12,13). However,
group). Cautious interpretation of these findings is
the occurrence of stent thrombosis tends to cluster
nonetheless required in light of the nonrandomized
within
(26,27),
study design and the likely imperfect adjustment for
emphasizing the need for adequate antiplatelet pro-
the
early
period
following
PCI
unmeasured baseline confounders in this observa-
tection early post-PCI. Current recommendations
tional investigation.
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Duration of Triple Therapy and PCI Outcomes
T A B L E 4 Clinical Outcomes Within 1 Year in Relation to Prescribed Duration of Triple Antithrombotic Therapy
TAT 1 Month (n ¼ 245)
TAT >1 Month (n ¼ 323)
HR (95% CI)
p Value
Adjusted HR (95% CI)
Adjusted p Value
Primary endpoint*
22 (9.5)
39 (12.9)
0.72 (0.42–1.21)
0.21
1.07 (0.56–2.06)
0.84
Death
17 (7.3)
30 (9.9)
0.73 (0.40–1.32)
0.29
0.82 (0.39–1.75)
0.61 0.99
10 (4.3)
17 (5.8)
0.76 (0.35–1.65)
0.49
0.99 (0.37–2.68)
MI
Cardiac death
8 (3.6)
14 (4.6)
0.73 (0.31–1.75)
0.49
1.38 (0.46–4.13)
0.56
CVE (stroke and TIA)
2 (0.9)
6 (2.0)
0.43 (0.09–2.14)
0.30
1.01 (0.17–6.06)
0.99
Stroke
2 (0.9)
5 (1.7)
0.52 (0.10–2.67)
0.43
1.25 (0.19–8.12)
0.81
Death or MI
23 (9.9)
40 (13.1)
0.73 (0.44–1.23)
0.24
0.95 (0.50–1.82)
0.88
Death, MI, or stroke
24 (10.3)
43 (14.1)
0.71 (0.43–1.17)
0.18
0.95 (0.51–1.77)
0.86
Revascularization (any)
14 (6.3)
25 (8.4)
0.71 (0.37–1.36)
0.30
0.77 (0.32–1.87)
0.56
Stent thrombosis Definite
4 (1.8)
6 (1.9)
0.86 (0.24–3.05)
0.82
1.90 (0.41–8.85)
0.41
Probable
7 (3.0)
14 (4.5)
0.64 (0.26–1.59)
0.34
1.37 (0.47–3.99)
0.57
13 (5.6)
26 (8.6)
0.63 (0.33–1.23)
0.18
0.98 (0.43–2.27)
0.97
Secondary ischemic endpoint†
Definite/probable
18 (7.8)
33 (10.9)
0.69 (0.39–1.23)
0.21
1.12 (0.55–2.29)
0.76
Secondary bleeding endpoint (BARC $3)
11 (4.8)
15 (5.1)
0.95 (0.44–2.07)
0.90
0.62 (0.21–1.80)
0.37
TIMI bleeding 10 (4.4)
14 (4.7)
0.92 (0.41–2.08)
0.85
0.64 (0.21–1.96)
0.43
Major
Major or minor
5 (2.2)
7 (2.4)
0.93 (0.29–2.92)
0.89
1.36 (0.31–5.88)
0.68
Minor
5 (2.2)
8 (2.7)
0.81 (0.26–2.47)
0.71
0.32 (0.06–1.61)
0.17
Depicted are numbers of first events (% from Kaplan-Meier estimate), and HRs with 95% CIs from Cox regressions. Adjusted HR (95% CI) from Cox regression adjusting for sex, clinical presentation with ACS, HAS-BLED score, use of any DES, and multiple-lesion treatment. *Cardiac death, MI, stroke, definite stent thrombosis, or TIMI major bleeding. †Cardiac death, MI, stroke, or definite stent thrombosis. BARC ¼ Bleeding Academic Research Consortium; CI ¼ confidence interval; CVE ¼ cerebrovascular event; HR ¼ hazard ratio; TIA ¼ transient ischemic attack; TIMI ¼ Thrombolysis in Myocardial Infarction; other abbreviations as in Table 1.
The findings of this study complement the results
patient groups (18)—support a role for short TAT
of the ISAR-TRIPLE trial (18), which showed similar
duration accounting for individual patient ischemic
clinical outcomes at 9-month follow-up in patients
and bleeding risks. This concept is corroborated in
treated with 6-week versus 6-month TAT following
the present real-world cohort, in which treatment
PCI with DES. The findings of ISAR-TRIPLE—in which
guidance was guided by clinical judgment and was
TAT duration was randomly allocated and thrombo-
patient tailored, as reflected by the fact that three-
embolic risk scores were well balanced between
quarters of patients with HAS-BLED scores $3 were
F I G U R E 2 Kaplan-Meier Event Rates for the Primary Endpoint
Cumulative incidence of the primary endpoint (A) and landmark analysis set at 30 days (B) in patients discharged on 1-month or longer duration of triple antithrombotic therapy (TAT). CI ¼ confidence interval; HR ¼ hazard ratio.
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Duration of Triple Therapy and PCI Outcomes
F I G U R E 3 Kaplan-Meier Event Rates for Bleeding Outcomes
Cumulative incidence of the secondary bleeding endpoint, Bleeding Academic Research Consortium (BARC) $3 bleeding (A) and TIMI (Thrombolysis In Myocardial Infarction) major bleeding during 1 year (C) with landmark analyses at 30 days (B and D, respectively) in patients discharged on 1-month or longer duration of triple antithrombotic therapy (TAT). CI ¼ confidence interval; HR ¼ hazard ratio.
discharged on short-term TAT, and a similar propor-
TAT cessation in the 1-month treatment group.
tion of patients with HAS-BLED scores #2 were
Although it is not possible to disentangle medication-
planned to receive longer term TAT (Figure 1C). Of
related from patient-related effects in this non-
note, 3-month treatment was prescribed in more
randomized investigation, these findings likely relate
than one-half of patients in the longer duration TAT
to physician guidance, avoiding prolonged TAT in
group (i.e., shorter than the 6-month duration in ISAR-
patients at increased bleeding risk. Focusing on the
TRIPLE) (18). The maximal extent to which TAT can be
time frame between 1 and 12 months, it is reasonable
safely reduced, also in conjunction with patient- and
to assume that higher patient-specific bleeding sus-
device-specific factors, requires further investigation.
ceptibility in patients treated with 1-month TAT may
Long-term exposure to TAT has been consistently
have counterbalanced the protective effect of an
linked to higher bleeding risk compared with less
earlier transition to less intensive regimens (mostly
intensive regimens (14–16,28). In this study, shorter
OAC plus antiplatelet monotherapy). This interpre-
TAT duration was not associated with a reduction of
tation is nonetheless speculative and requires further
clinically relevant bleeding complications throughout
investigation in a prospective fashion, accounting for
1 year compared with more extended TAT treatment.
different bleeding risks in conjunction with differing
This finding held true in landmark analyses following
antithrombotic treatment durations.
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Duration of Triple Therapy and PCI Outcomes
F I G U R E 4 Kaplan-Meier Event Rates for the Secondary Ischemic Endpoint
Cumulative incidence of the composite of cardiac death, myocardial infarction (MI), stroke, or definite stent thrombosis (A) and landmark analysis at 30 days (B) in patients discharged on 1-month or longer duration of triple antithrombotic therapy (TAT). CI ¼ confidence interval; HR ¼ hazard ratio.
The finding of nondiffering ischemic outcomes
and 12 months (31) or following DAPT cessation (26).
associated with 1-month TAT is reassuring but re-
Randomized trials adequately powered to assess
quires cautious interpretation, in view of the modest
ischemic outcomes, including the PIONEER AF-PCI
sample size and observational nature of this study.
(A Study Exploring Two Strategies of Rivaroxaban
Notably, patients in the longer TAT group were likely
[JNJ39039039; BAY-59-7939] and One of Oral Vitamin
at higher ischemic risk, as reflected by a higher fre-
K Antagonist in Patients With Atrial Fibrillation
quency of ACS and particularly ST-segment elevation
Who Undergo Percutaneous Coronary Intervention;
MI at baseline. In this context, the trend toward a
NCT01830543) and the REDUAL-PCI trial (Evaluation
higher MI rate in the long-TAT group within the first
of Dual Therapy With Dabigatran vs. Triple Therapy
month (i.e., during the time frame when anti-
With Warfarin in Patients With AF That Undergo a
thrombotic treatment modes did not differ between
PCI With Stenting; NCT02164864), are currently
groups) (Online Table 1) suggests a possible effect
investigating optimal combinations and durations
of patient-related factors on outcomes. However,
of antiplatelet agents, warfarin, and novel OAC
the small number of 30-day events and the non-
medications.
randomized study design limit the ability to draw
Omission of aspirin has been proposed as a means
definitive conclusions in this respect. It should also be
of mitigating the bleeding hazard of TAT (14–16). In
noted that BMS were used in 25% of patients treated
the WOEST (What Is the Optimal Antiplatelet &
with 1-month TAT, although results did not differ after
Anticoagulant Therapy in Patients With Oral Anti-
adjustment for stent type. The present findings are
coagulation and Coronary Stenting) trial, patients
in line with evidence of comparable ischemic out-
randomized to OAC plus clopidogrel versus TAT had
comes in orally anticoagulated patients when DAPT
lower rates of any bleeding but similar TIMI major
duration following PCI with DES was shortened to the
bleeding, similar ischemic events, and reduced mor-
duration generally recommended for BMS (18). Along
tality (14). A large, nationwide registry reported
the
(Zotarolimus-Eluting
higher rates of bleeding with TAT compared with
Endeavor Sprint Stent in Uncertain DES Candidates)
same
lines,
the
ZEUS
OAC, alone or in combination with antiplatelet mon-
trial showed no signal of risk in patients who were at
otherapy, without difference in thromboembolic risk
high bleeding and/or ischemic risk (including patients
(16). Although these investigations provided valuable
treated with OAC) despite shortening of DAPT to 30
insights, they compared prolonged, 1-year TAT
days after PCI with new-generation DES (29). Evidence
treatment (which is expected to increase bleeding
from nonanticoagulated patients appears to support
complications) and, in contrast to the present study,
shorter DAPT regimens following PCI with new-
assessed TAT in a binary fashion (i.e., not addressing
generation DES (30) and indicates similar risks
differing TAT durations with subsequent transi-
for stent thrombosis for DES versus BMS between 1
tion to less intensive regimens, as is currently
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Duration of Triple Therapy and PCI Outcomes
F I G U R E 5 Subgroup Analyses for the Primary and Secondary Endpoints
Stratified analyses of 1-year clinical outcomes in relation to clinical presentation, treatment with any drug-eluting stent (DES), and atrial fibrillation as main indication for oral anticoagulation. Depicted are number of first events (percentage from Kaplan-Meier estimate), and hazard ratios (HRs) (95% confidence intervals [CIs]) from Cox regressions. ACS ¼ acute coronary syndrome(s); CAD ¼ coronary artery disease; TAT ¼ triple antithrombotic therapy.
recommended). The combination of OAC plus clopi-
treatment durations pertain to prescription times
dogrel may be considered as an alternative to TAT for
at discharge, because the actual treatment duration
selected patients with high bleeding and low ischemic
was not consistently recorded. Although multivariate
risk (7); this therapeutic option could not be tested in
adjustments were performed to account for baseline
the present study.
differences, the effect of unmeasured baseline confounders cannot be excluded. The findings of the
STUDY LIMITATIONS. This study had several limita-
exploratory analyses are presented as hypothesis
tions attributable to its observational nature. First,
generating only; prospective studies are needed to
the registry was not designed to evaluate clinical
definitively address the contribution of different
outcomes in relation to TAT; however, ischemic and
antithrombotic
bleeding events were prospectively defined outcome
impact of patient-specific ischemic and bleeding risks
treatment
durations
versus
the
measures and were specifically evaluated during
on clinical outcomes. This study could not assess the
1-year follow-up. The duration of TAT was not pre-
role of less intensive antithrombotic regimens (e.g.,
defined but was individualized by physician judg-
OAC plus antiplatelet monotherapy); ongoing trials
ment; our findings nonetheless reflect real-world
are expected to address these issues. The present
practice, and treatment was tailored to individual
findings are applicable to TAT including clopidogrel,
patient risk, as is recommended in current guidelines.
because the number of patients treated with more
A notable limitation is the fact that that reported
potent P2Y 12 inhibitors was too small to allow a
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Duration of Triple Therapy and PCI Outcomes
meaningful subanalysis; the impact of prasugrel as part of TAT regimens has been addressed in studies including more prasugrel-treated patients (28,32). The difference of prescribed TAT duration between groups was small; this may have limited the ability to detect differences in outcomes in relation to treatment duration.
undergoing PCI, 1-month TAT was associated with similar bleeding, ischemic, and net clinical outcomes compared with longer TAT durations throughout 1 year in this observational study. Reducing the duration of TAT to 1 month appears to be a reasonable option in patients with high bleeding risk. These findings require confirmation in prospective studies regimens
of
pre-specified
lengths
tailored to individual patient ischemic and bleeding risks. REPRINT
who require OAC who undergo PCI. Although triple therapy is recommended to be limited in duration in current consensus documents, there are few data OAC plus DAPT.
Among patients with clinical indications for OAC
TAT
WHAT IS KNOWN? TAT is indicated for patients
addressing the optimal length of the combination of
CONCLUSIONS
testing
PERSPECTIVES
WHAT IS NEW? In this observational study of 568 unselected patients undergoing PCI, we found similar ischemic events, bleeding events, and net clinical outcomes associated with abbreviated, 1-month duration versus more prolonged duration of triple therapy. These findings held true in analyses stratified for clinical presentation with stable CAD versus ACS and for interventions using DES versus BMS. WHAT IS NEXT? Data from larger, prospective studies are needed to determine clinical outcomes in relation to pre-specified triple-therapy durations
REQUESTS
AND
CORRESPONDENCE:
Dr. Lorenz Räber, Bern University Hospital, Department of Cardiology, Freiburgstrasse, Bern 3010, Switzerland.
tailored to individual patient ischemic and bleeding risks and to assess the role of novel oral anticoagulant medications in this clinical setting.
E-mail: [email protected].
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Investigators. A clinical trial comparing three antithrombotic-drug regimens after coronaryartery stenting. N Engl J Med 1998;339:1665–71. 6. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334: 1084–9. 7. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/ EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2014;35:2541–619. 8. Roffi M, Patrono C, Collet JP, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation. Eur Heart J 2016;37:267–315. 9. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1–76. 10. Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with
atrial fibrillation. Arch Intern Med 2010;170: 1433–41. 11. Holmes DR Jr., Kereiakes DJ, Kleiman NS, et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009;54:95–109. 12. Zhao HJ, Zheng ZT, Wang ZH, et al. “Triple therapy” rather than “triple threat”: a metaanalysis of the two antithrombotic regimens after stent implantation in patients receiving longterm oral anticoagulant treatment. Chest 2011; 139:260–70. 13. Ruiz-Nodar JM, Marin F, Hurtado JA, et al. Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation; implications for bleeding risk and prognosis. J Am Coll Cardiol 2008;51:818–25. 14. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–15. 15. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013;62: 981–9. 16. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic
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drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012;126:1185–93.
all-comer stent trials: balancing sensitivity and specificity. Addendum to the historical MI definitions used in stent studies. Eurointervention 2010; 5:871–4.
17. Paikin JS, Wright DS, Crowther MA, Mehta SR, Eikelboom JW. Triple antithrombotic therapy in
23. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials:
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a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736–47.
18. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE trial. J Am Coll Cardiol 2015;65: 1619–29.
24. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51: 690–7.
19. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coro-
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undergoing percutaneous coronary interventions. Circ Cardiovasc Interv 2015;8. e002053.
20. Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013;61:2060–6.
26. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013;382:1714–22.
21. Cutlip DE, Windecker S, Mehran R, et al., for the Academic Research Consortium. Clinical end
27. Räber L, Magro M, Stefanini GG, et al. Very late coronary stent thrombosis of a newer-generation
points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: 2344–51.
everolimus-eluting stent compared with earlygeneration drug-eluting stents: a prospective cohort study. Circulation 2012;125:1110–21.
22. Vranckx P, Cutlip DE, Mehran R, et al. Myocardial infarction adjudication in contemporary
28. Jackson LR II, Ju C, Zettler M, et al. Outcomes of patients with acute myocardial infarction
undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a comparison of clopidogrel versus prasugrel from the TRANSLATE-ACS Study. J Am Coll Cardiol Intv 2015;8:1880–9. 29. Valgimigli M, Patialiakas A, Thury A, et al. Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates. J Am Coll Cardiol 2015;65:805–15. 30. Feres F, Costa RA, Abizaid A, et al. Three vs. twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510–22. 31. Bangalore S, Kumar S, Fusaro M, et al. Shortand long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation 2012;125:2873–91. 32. Verheugt FW. Do not use novel antiplatelet agents in patients on oral anticoagulants after stenting. J Am Coll Cardiol Intv 2015;8:1890–2.
KEY WORDS anticoagulation, antiplatelet, bleeding, coronary intervention A PP END IX For supplemental tables and a figure, please see the online version of this article.
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VOL. 9, NO. 14, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2016.04.027
Duration of Triple Antithrombotic Therapy and Outcomes Among Patients Undergoing Percutaneous Coronary Intervention Konstantinos C. Koskinas, MD, MSC,a Lorenz Räber, MD, PHD,a Thomas Zanchin, MD,a Thomas Pilgrim, MD,a Stefan Stortecky, MD,a Lukas Hunziker, MD,a Stefan Blöchlinger, MD,a Michael Billinger, MD,a Fabienne Gartwyl, BA,a Christina Moro, MA,a Aris Moschovitis, MD,a Peter Jüni, MD,b Dik Heg, PHD,c Stephan Windecker, MDa
ABSTRACT OBJECTIVES The aim of this study was to compare clinical outcomes in relation to the duration of triple antithrombotic therapy (TAT) among patients with indications for oral anticoagulation undergoing percutaneous coronary intervention (PCI). BACKGROUND TAT is recommended for patients undergoing PCI with a firm indication for oral anticoagulation. Duration of TAT may influence outcomes, but the optimal period of TAT remains uncertain. METHODS Between 2009 and 2013, 8,772 consecutive patients undergoing PCI for stable coronary artery disease or acute coronary syndrome were prospectively included in the Bern PCI Registry (NCT02241291). Of 568 patients with indications for oral anticoagulation, 245 (43%) were discharged on a regimen of 1-month TAT and 323 (57%) on a regimen >1-month TAT (mean 5.1 3.3 months, median 3 months). The primary endpoint was a composite of cardiac death, myocardial infarction, stroke, definite stent thrombosis, or TIMI (Thrombolysis in Myocardial Infarction) major bleeding within 1 year. RESULTS Patients on 1-month compared with >1-month TAT were more commonly women, with stable coronary artery disease, had higher HAS-BLED scores, and less frequently received drug-eluting stents. In multivariate analyses, the primary endpoint did not differ between groups (adjusted hazard ratio: 1.07; 95% confidence interval: 0.56 to 2.06; p ¼ 0.84). Results were consistent in stratified analyses in relation to clinical presentation with acute coronary syndrome (38%) and PCI with drug-eluting stents (79%) (p for interaction ¼ 0.18 and 0.95, respectively). There were no differences in the secondary bleeding endpoint, Bleeding Academic Research Consortium $3 bleeding (adjusted hazard ratio: 0.62; 95% confidence interval: 0.21 to 1.80; p ¼ 0.37) and the secondary composite ischemic endpoint (cardiac death, myocardial infarction, stroke, or definite stent thrombosis) (adjusted hazard ratio: 1.12; 95% confidence interval: 0.55 to 2.29; p ¼ 0.76). CONCLUSIONS One-month TAT, used preferentially in patients with higher estimated bleeding risk in this observational study, was associated with similar net clinical outcomes compared with longer TAT durations throughout 1 year following PCI. (J Am Coll Cardiol Intv 2016;9:1473–83) © 2016 by the American College of Cardiology Foundation.
From the aDepartment of Cardiology, Bern University Hospital, Bern, Switzerland; bDepartment of Medicine, University of Toronto, Toronto, Canada; and the cInstitute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. Dr. Jüni is an unpaid steering committee or statistical executive committee member of trials funded by Abbott Vascular, Biosensors, Medtronic, and St. Jude Medical. Prof. Windecker has received research contracts to the institution from Abbott Vascular, AstraZeneca, Boston Scientific, Biosensors, Biotronik, Cordis, Eli Lilly, Medtronic, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Koskinas and Räber contributed equally to this work. Manuscript received February 3, 2016; revised manuscript received March 30, 2016, accepted April 21, 2016.
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U
ABBREVIATIONS AND ACRONYMS
p to 10% of patients undergoing
METHODS
percutaneous coronary intervention (PCI) have concomitant indica-
PATIENT POPULATION. This was a retrospective
tions for oral anticoagulation (OAC) (1,2). The
analysis of prospectively collected data. All consecu-
therapeutic targets of OAC protecting against
tive patients undergoing PCI for stable coronary artery
ischemic complications related to fibrin-rich
disease (CAD) or acute coronary syndrome (ACS)
thrombus in patients with atrial fibrillation
at Bern University Hospital (Bern, Switzerland) as
(AF) or mechanical valves (3,4) versus dual-
of 2009 were prospectively entered into the Bern
antiplatelet therapy (DAPT) for prevention
PCI Registry (NCT02241291). The present analysis
of platelet-dependent stent thrombosis (5,6)
included all consecutive patients with clinical in-
are
on
dications for OAC who were discharged on TAT. Per
different pathobiological pathways. There-
default, most patients requiring OAC at our institution
fore, a combination of OAC plus DAPT is
receive
plausible among patients with indications for
following PCI instead of less intensive antithrombotic
OAC = oral anticoagulation
OAC undergoing PCI and is currently recom-
regimens (e.g., OAC plus antiplatelet monotherapy).
PCI = percutaneous coronary
mended in consensus documents (1,7–9).
In line with the inclusive character of the registry,
Triple antithrombotic therapy (TAT), the
there were no formal exclusion criteria. Demographic
combination of OAC and DAPT, is associated
and clinical characteristics, information on performed
with increased bleeding risk (10,11) but is
interventions, and hospital outcome data were sys-
more effective than DAPT alone for reduction of
tematically collected. Scores of HAS-BLED (hyper-
major adverse cardiovascular events in these patients
tension, abnormal liver or renal function, stroke or
(1,12,13).
thromboembolism, bleeding history, elderly [age >65
ACS = acute coronary syndrome(s)
AF = atrial fibrillation BMS = bare-metal stent(s) CAD = coronary artery disease CI = confidence interval DAPT = dual-antiplatelet therapy
DES = drug-eluting stent(s) HR = hazard ratio MI = myocardial infarction
intervention
TAT = triple antithrombotic therapy
complementary
and
dependent
intensive
antithrombotic
DAPT
of
differing
duration
years], drug consumption or alcohol abuse) were
SEE PAGE 1484
Less
additional
calculated, excluding labile international normalized regimens
(e.g.,
ratio values, which were not collected. The registry
omission of aspirin) have received attention as a po-
was approved by the institutional ethics committee,
tential means of mitigating bleeding risk (14–16) and
and patients provided written informed consent to
may be considered as an alternative to TAT in selected
undergo prospective follow-up.
patients (1,7,8). Abbreviated regimens of TAT may be explored as an alternative strategy to optimize the benefit-to-risk ratio in view of the fact that bleeding associated with TAT appears to be exposure dependent and related to treatment duration (17). In this context, the ISAR-TRIPLE (Intracoronary Stenting and Antithrombotic Regimen–Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment Regimen in Patients With Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting) randomized trial reported comparable net clinical outcomes with 6-week versus 6-month TAT following PCI with drugeluting stent (DES), supporting the role of shorter TAT duration in this setting (18). The length of TAT is currently recommended to be adjusted according to individual thrombotic and bleeding risk, clinical presentation, and type of stent; these recommendations remain largely consensus rather than evidence based, as reflected by the low level of evidence and differences
PROCEDURES. PCI was performed in accordance with
current practice guidelines (7). Periprocedural management, including interrupted versus uninterrupted OAC, dose of unfractionated heparin, or use of glycoprotein IIb/IIIa inhibitors, was left to the discretion of the operator. DAPT consisting of acetylsalicylic acid and a P2Y12 inhibitor was initiated before, at the time of, or immediately after the procedure. The P2Y 12 inhibitor of choice was clopidogrel in the majority of patients. Ticagrelor or prasugrel was administered if deemed clinically necessary by the treating physician in certain cases of ACS, complex anatomy, or complicated interventions; prasugrel was selectively used before the excessive bleeding risk for TAT including prasugrel was reported (20). The duration of DAPT was not uniformly specified but individualized accounting for each patient’s clinical presentation, ischemic and bleeding risk profile.
between European (1,7,8) and North American guide-
PATIENT FOLLOW-UP. Patients were systematically
lines regarding specific TAT durations (19).
followed at discharge and throughout 1 year to assess
Against this background, the purpose of the pres-
adverse cardiac and cerebrovascular events. Survival
ent observational study was to compare clinical out-
data were obtained from hospital records and
comes in relation to a regimen of 1-month versus
municipal civil registries. A health questionnaire was
more prolonged TAT in a cohort of unselected pa-
sent to all living patients with questions on rehospi-
tients undergoing PCI with indications for OAC.
talization, medical treatment, and adverse events,
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followed by telephone contact in case of missing response. General practitioners, referring cardiolo-
F I G U R E 1 Frequency Distribution of Triple-Antithrombotic Therapy Durations
gists, and patients were contacted, and external medical records, discharge letters, and coronary angiography
documentation
were
systematically
reviewed as necessary for additional information. Medical treatment was recorded during index PCI, at discharge, and at 1 year. CLINICAL ENDPOINTS AND STUDY ASSESSMENTS.
A clinical event committee consisting of 2 cardiologists (and in case of disagreement of a third referee) adjudicated all events using original source documents. Cardiac death was defined as any death due to an immediate cardiac cause, procedure-related mortality, and death of unknown cause. Stent thrombosis and myocardial infarction (MI) were defined according to the Academic Research Consortium criteria (21) and the modified historical definition (22), respectively. Stroke was defined as rapid development of clinical signs of focal or global disturbance of cerebral function lasting >24 h with imaging evidence of acute, clinically relevant brain lesion. Bleeding events were categorized according to the Bleeding Academic Research Consortium (BARC) and TIMI (Thrombolysis In Myocardial Infarction) classifications (23). For this analysis, patients were categorized into those discharged with 1-month versus more prolonged (>1 month) TAT following PCI. Categorization was based on prescription times at discharge and
One-month triple antithrombotic therapy (TAT) was prescribed to 43% of all patients (A,B) but 76% of patients with HAS-BLED scores $3 (C).
not actual duration of treatment. The primary endpoint was a composite of cardiac death, MI,
College Station, Texas). Continuous variables are
stroke, definite stent thrombosis, or TIMI major
summarized as mean SD or median (interquartile
bleeding. The rationale for a combined ischemic and
range) and categorical variables as actual numbers and
bleeding endpoint is in line with the primary assess-
percentages. Baseline and procedural characteristics
ment of the ISAR-TRIPLE trial (18) (currently the only
and medications were compared using Fisher exact
randomized trial comparing different TAT durations
tests for binary responses, chi-square tests for more
post-PCI),
recognizing
that
both
ischemic
and
than 2 responses, unpaired Student t tests for means,
bleeding complications adversely affect prognosis
and Mann-Whitney U tests for medians. Clinical out-
following PCI (24). The secondary bleeding endpoint
comes were analyzed using Cox regression analysis
was BARC $3 bleeding; the secondary ischemic
(time to first event). All adjusted models were based on
endpoint was the composite of cardiac death, MI,
20 datasets created using chained equations to impute
stroke, or definite stent thrombosis.
missing date (estimates combined using Rubin’s rule).
The main analysis compared outcomes within
Subsequently, adjustment was made for the following
12 months in relation to prescribed TAT duration.
baseline covariates: sex, clinical presentation with
Exploratory analyses included: 1) landmark analyses
ACS, HAS-BLED score, use of any DES, and multiple-
set at 30 days (i.e., focusing on the period after
lesion treatment. Findings were considered statisti-
expected TAT cessation in the short-duration group);
cally significant at the 0.05 level.
2)
sensitivity
analyses
excluding
patients
with
ST-segment elevation MI as well as those receiving prasugrel or ticagrelor; and 3) stratified analyses in relation to stent type and clinical presentation.
RESULTS Between March 2009 and December 2013, 8,772
STATISTICAL ANALYSES. Statistical analyses were
consecutive patients undergoing PCI were included in
performed with Stata version 14.0 (StataCorp LP,
the Bern PCI Registry. Of 568 patients with clinical
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Duration of Triple Therapy and PCI Outcomes
(n ¼ 448 [79%]) received new-generation DES.
T A B L E 1 Baseline Characteristics of the Study Population
Age, yrs
Patients with 1-month TAT were more commonly
TAT 1 Month (n ¼ 245)
TAT >1 Month (n ¼ 323)
73.4 8.9
72.5 10.0
p Value
0.261
treated with bare-metal stents (BMS) or balloon angioplasty without stents. Medication use during index procedure, at discharge, and at 1-year follow-up
Male
179 (73.1)
259 (80.2)
0.055
Body mass index, kg/m2
28.2 5.5
28.0 5.2
0.64
Diabetes mellitus
63 (25.8)
107 (33.2)
0.06
glycoprotein IIb/IIIa inhibitors during the index pro-
Hypertension
190 (78.5)
254 (79.4)
0.83
cedure, more commonly received clopidogrel, and
Dyslipidemia
168 (69.1)
206 (64.4)
0.24
less frequently received prasugrel at discharge.
Current smoker
30 (12.4)
51 (16.2)
0.23
is summarized in Table 3. Patients with 1-month versus longer term TAT less frequently received
Cardiovascular risk factors
Renal dysfunction
86/222 (38.7)
94/281 (33.5)
0.22
CLINICAL OUTCOMES IN RELATION TO TAT DURATION.
Anemia
62/214 (29.0)
96/286 (33.6)
0.29
Clinical outcomes within 30 days are summarized in
Thrombocytopenia
30/214 (14.0)
32/281 (11.4)
0.41
Online Table 1. At 12 months, complete follow-up was
Previous MI
56 (22.9)
75 (23.2)
1.00
available in 533 patients (93.8%) (Online Table 2). At
Previous PCI
75 (30.7)
89 (27.6)
0.45
Previous CABG
47 (19.2)
62 (19.2)
1.00
Clinical presentation Stable CAD Unstable angina NSTEMI STEMI
0.001
Pulmonary embolism Mechanical valve
in 22 patients (9.5%) discharged on 1-month TAT and
171 (69.8)
182 (56.3)
0.001
in 39 patients (12.9%) with longer TAT (hazard ratio
14 (5.7)
15 (4.6)
0.57
[HR]: 0.72; 95% confidence interval [CI]: 0.42 to 1.21;
46 (18.8)
80 (24.8)
0.10
p ¼ 0.21) (Table 4). Differences were not significant in
14 (5.7)
46 (14.2)
0.001
multivariate analysis (adjusted HR: 1.07; 95% CI: 0.56
138 (56.3)
177 (55.3)
0.86
29 (11.8)
28 (8.8)
0.26
8 (3.3)
17 (5.3)
0.30
Indication for OAC Atrial fibrillation
1 year, the primary composite endpoint had occurred
to 2.06; p ¼ 0.84) (Figure 2A) as well as in a landmark analysis between 1 and 12 months (adjusted HR: 0.89; 95% CI: 0.48 to 1.66; p ¼ 0.72) (Figure 2B). Rates of the
Deep venous thrombosis
14 (5.7)
20 (6.3)
0.86
secondary bleeding endpoint, BARC $3 bleeding
LVEF <30% or LV thrombus
28 (11.4)
38 (11.9)
0.89
(adjusted HR: 0.62; 95% CI: 0.21 to 1.80; p ¼ 0.37) or
9 (3.7)
16 (5.0)
0.54
TIMI major bleeding, were similar, also in landmark
HAS-BLED score
2.8 0.9
1.9 0.7
<0.001
analyses set at 1 month (Figure 3). We found no sig-
HAS-BLED score $3
138 (56.3)
43 (13.3)
<0.001
nificant differences regarding the combined ischemic
Miscellaneous
Values are mean SD or count (%). The p values are from Fisher exact tests (2 categories), chi-square tests (clinical presentation), and unpaired Student t tests (age, body mass index, and HAS-BLED score). CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; OAC ¼ oral anticoagulation; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction; TAT ¼ triple antithrombotic therapy.
endpoint (adjusted HR: 1.12; 95% CI: 0.55 to 2.29; p ¼ 0.76) (Figure 4) or its individual components (cardiac death, MI, stroke, or definite stent thrombosis) (Table 4). Results were consistent in sensitivity analyses excluding patients who were discharged with prasugrel or ticagrelor as part of TAT (n ¼ 15; 1 in the 1-month TAT group and 14 in the >1-month TAT group) (Online Table 3), as well as after the exclusion
indications for OAC who received TAT, 245 (43.1%)
of patients with ST-segment elevation MI (i.e.,
were discharged on TAT for 1 month and 323 (56.9%)
patients at presumed highest thrombotic risk) (Online
for >1 month (median 3 months; interquartile range: 3
Table 4). The primary endpoint did not differ significantly
to 6 months) (Figure 1). BASELINE CHARACTERISTICS. Baseline characteris-
tics are summarized in Table 1. The most common indication for OAC was AF (55%). Patients discharged with
1-month
versus
longer
TAT
were
more
commonly women, presented more often with stable CAD, had higher HAS-BLED scores (2.8 0.9 vs. 1.9 0.7; p < 0.001), and more frequently had HAS-BLED scores $3 (56.3% vs. 13.3%; p < 0.001).
in relation to TAT duration in exploratory analyses stratified for stable CAD versus ACS (p for interaction ¼ 0.18), PCI with or without DES (p for interaction ¼ 0.95), and AF as the primary indication for OAC (p for interaction ¼ 0.55) (Figure 5). Similarly, no difference was observed in stratified analyses for the secondary ischemic and bleeding endpoints (Figure 5) and for TIMI major bleeding (Online Figure 1).
Short (1-month) TAT duration was prescribed in 76.2% of patients with HAS-BLED scores $3 and in 27.6% of
DISCUSSION
patients with HAS-BLED scores #2 (Figure 1C). Procedural characteristics during the index inter-
Although TAT is currently recommended for patients
vention are shown in Table 2. The majority of patients
with indications for OAC who undergo PCI, optimal
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Duration of Triple Therapy and PCI Outcomes
T A B L E 2 Procedural Characteristics
T A B L E 3 Medications During Percutaneous Coronary Intervention, at
Discharge, and at 1 Year
TAT 1 Month (n ¼ 245)
TAT >1 Month (n ¼ 323)
383
554
Number of lesions per patient
1.6 0.9
1.7 0.9
0.16
Multiple-lesion treatment
98 (40.0)
152 (47.1)
0.10
Number of lesions
Balloon angioplasty
0.016 522 (94.4)
39 (10.2)
31 (5.6)
207 (60.2)
503 (96.4)
<0.001
3 (0.9)
69 (13.2)
<0.001
Everolimus eluting
112 (32.6)
245 (46.9)
0.002
BP sirolimus eluting
61 (17.7)
104 (19.9)
0.57
Mean stent diameter, mm per lesion
Abciximab
Clopidogrel
Biolimus eluting
Total stent length, mm per lesion
Glycoprotein IIb/IIIa inhibitors
None
New-generation DES
Zotarolimus eluting
TAT >1 Month (n ¼ 323)
238 (97.1)
313 (97.8)
4 (1.6)
15 (4.7)
0.06
4 (1.6)
14 (4.4)
0.09
12 (5.0)
25 (7.9)
0.17
Loading dose 344 (89.8)
Stent type per lesion*
Bare metal
TAT 1 Month (n ¼ 245)
33 (9.6)
85 (16.3)
0.035
137 (39.8)
19 (3.6)
<0.001
3.0 0.5
2.9 0.5
0.012
22.4 14.0
24.6 14.0
0.033
Values are mean SD or count (%). The p values are from Poisson regression (number of lesions), Fisher exact test (multiple-lesion treatment), or otherwise cluster-robust general or generalized linear models accounting for lesions nested within patients. *Mixing stents of different types inside the same lesion explains double counting. BP ¼ biodegradable polymer; DES ¼ drug-eluting stent(s); TAT ¼ triple antithrombotic therapy.
0.79
0.28 216 (89.3)
265 (83.9)
0.08
Prasugrel
4 (1.7)
11 (3.5)
0.29
Ticagrelor
10 (4.1)
12 (3.8)
0.83
Clopidogrel and prasugrel
0 (0.0)
2 (0.6)
0.51
Clopidogrel and ticagrelor
0 (0.0)
1 (0.3)
1.00
At discharge Acetylsalicylic acid
245 (100.0)
323 (100)
Clopidogrel
244 (99.5)
311 (96.3)
0.03
7 (2.2)
0.02
7 (2.2)
0.15
Prasugrel Ticagrelor
0 (0.0) 1 (0.4)
Any dual-antiplatelet therapy
245 (100)
323 (100.0)
Oral anticoagulation
245 (100)
323 (100)
232 (94.7)
317 (98.1)
0.04
13 (5.3)
6 (1.9)
0.03
Vitamin K antagonist Novel oral anticoagulation At 1 yr Acetylsalicylic acid
167/209 (79.9)
218/264 (82.6)
0.48
55/209 (26.3)
91/264 (34.5)
0.06
Prasugrel
3/209 (1.4)
4/264 (1.5)
1.00
Ticagrelor
0/209 (0.0)
1/264 (0.4)
1.00
45/209 (21.5)
62/261 (23.5)
0.66
167/208 (80.3)
205/261 (78.6)
157/208 (75.5)
192/261 (73.6)
0.67
10/208 (4.8)
13/261 (5.0)
1.00
Clopidogrel
Any dual-antiplatelet therapy
duration of TAT treatment is not well established (1).
p Value
During PCI Unfractionated heparin
Type of intervention per lesion Stenting
p Value
Oral anticoagulation
The main finding of this observational study is that an
Vitamin K antagonist
abbreviated, 1-month duration of TAT, determined by
Novel oral anticoagulation
treating physicians according to individual patient risk profiles, was associated with similar bleeding and ischemic complications and net clinical outcomes
Values are count (%). The p values are from Fisher exact tests (2 categories) or chi-square test (loading dose). TAT ¼ triple antithrombotic therapy.
throughout 1 year compared with more prolonged TAT regimens. Notwithstanding inherent limitations of nonrandomized investigations, these findings add
advocate patient-tailored reduction of TAT duration
to evidence indicating that shorter, patient-tailored
and specifically to 1 month in patients at high
DAPT durations assume a role in the management of
bleeding risk (e.g., HAS-BLED score $3) or presenting
orally anticoagulated patients undergoing coronary
with stable CAD (1,7,8). Our finding of similar net
interventions (18). They also support current, largely
clinical outcomes with short (1-month) compared
consensus-based recommendations regarding the
with longer TAT adds new evidence in support of
length of TAT treatment in this specific clinical
expert consensus statements and consistent guide-
setting (1,7–9,19).
lines (1,7–9,19). These results held true after multi-
In patients who require OAC and receive coronary
variate adjustments including clinical presentation
stents, balancing the ischemic versus bleeding hazard
and stent type as well as in sensitivity analyses
remains a challenging task. Long-term TAT increases
focusing on patients with ACS, those with AF as
the risk for bleeding, including major and fatal
an indication for OAC, and those treated with DES
bleeding (14–16,25), but may be more effective and in
(i.e., more than one-half of patients in the 1-month
selected studies appeared to improve patient out-
and >90% of patients in the longer term TAT
comes compared with DAPT alone (12,13). However,
group). Cautious interpretation of these findings is
the occurrence of stent thrombosis tends to cluster
nonetheless required in light of the nonrandomized
within
(26,27),
study design and the likely imperfect adjustment for
emphasizing the need for adequate antiplatelet pro-
the
early
period
following
PCI
unmeasured baseline confounders in this observa-
tection early post-PCI. Current recommendations
tional investigation.
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Duration of Triple Therapy and PCI Outcomes
T A B L E 4 Clinical Outcomes Within 1 Year in Relation to Prescribed Duration of Triple Antithrombotic Therapy
TAT 1 Month (n ¼ 245)
TAT >1 Month (n ¼ 323)
HR (95% CI)
p Value
Adjusted HR (95% CI)
Adjusted p Value
Primary endpoint*
22 (9.5)
39 (12.9)
0.72 (0.42–1.21)
0.21
1.07 (0.56–2.06)
0.84
Death
17 (7.3)
30 (9.9)
0.73 (0.40–1.32)
0.29
0.82 (0.39–1.75)
0.61 0.99
10 (4.3)
17 (5.8)
0.76 (0.35–1.65)
0.49
0.99 (0.37–2.68)
MI
Cardiac death
8 (3.6)
14 (4.6)
0.73 (0.31–1.75)
0.49
1.38 (0.46–4.13)
0.56
CVE (stroke and TIA)
2 (0.9)
6 (2.0)
0.43 (0.09–2.14)
0.30
1.01 (0.17–6.06)
0.99
Stroke
2 (0.9)
5 (1.7)
0.52 (0.10–2.67)
0.43
1.25 (0.19–8.12)
0.81
Death or MI
23 (9.9)
40 (13.1)
0.73 (0.44–1.23)
0.24
0.95 (0.50–1.82)
0.88
Death, MI, or stroke
24 (10.3)
43 (14.1)
0.71 (0.43–1.17)
0.18
0.95 (0.51–1.77)
0.86
Revascularization (any)
14 (6.3)
25 (8.4)
0.71 (0.37–1.36)
0.30
0.77 (0.32–1.87)
0.56
Stent thrombosis Definite
4 (1.8)
6 (1.9)
0.86 (0.24–3.05)
0.82
1.90 (0.41–8.85)
0.41
Probable
7 (3.0)
14 (4.5)
0.64 (0.26–1.59)
0.34
1.37 (0.47–3.99)
0.57
13 (5.6)
26 (8.6)
0.63 (0.33–1.23)
0.18
0.98 (0.43–2.27)
0.97
Secondary ischemic endpoint†
Definite/probable
18 (7.8)
33 (10.9)
0.69 (0.39–1.23)
0.21
1.12 (0.55–2.29)
0.76
Secondary bleeding endpoint (BARC $3)
11 (4.8)
15 (5.1)
0.95 (0.44–2.07)
0.90
0.62 (0.21–1.80)
0.37
TIMI bleeding 10 (4.4)
14 (4.7)
0.92 (0.41–2.08)
0.85
0.64 (0.21–1.96)
0.43
Major
Major or minor
5 (2.2)
7 (2.4)
0.93 (0.29–2.92)
0.89
1.36 (0.31–5.88)
0.68
Minor
5 (2.2)
8 (2.7)
0.81 (0.26–2.47)
0.71
0.32 (0.06–1.61)
0.17
Depicted are numbers of first events (% from Kaplan-Meier estimate), and HRs with 95% CIs from Cox regressions. Adjusted HR (95% CI) from Cox regression adjusting for sex, clinical presentation with ACS, HAS-BLED score, use of any DES, and multiple-lesion treatment. *Cardiac death, MI, stroke, definite stent thrombosis, or TIMI major bleeding. †Cardiac death, MI, stroke, or definite stent thrombosis. BARC ¼ Bleeding Academic Research Consortium; CI ¼ confidence interval; CVE ¼ cerebrovascular event; HR ¼ hazard ratio; TIA ¼ transient ischemic attack; TIMI ¼ Thrombolysis in Myocardial Infarction; other abbreviations as in Table 1.
The findings of this study complement the results
patient groups (18)—support a role for short TAT
of the ISAR-TRIPLE trial (18), which showed similar
duration accounting for individual patient ischemic
clinical outcomes at 9-month follow-up in patients
and bleeding risks. This concept is corroborated in
treated with 6-week versus 6-month TAT following
the present real-world cohort, in which treatment
PCI with DES. The findings of ISAR-TRIPLE—in which
guidance was guided by clinical judgment and was
TAT duration was randomly allocated and thrombo-
patient tailored, as reflected by the fact that three-
embolic risk scores were well balanced between
quarters of patients with HAS-BLED scores $3 were
F I G U R E 2 Kaplan-Meier Event Rates for the Primary Endpoint
Cumulative incidence of the primary endpoint (A) and landmark analysis set at 30 days (B) in patients discharged on 1-month or longer duration of triple antithrombotic therapy (TAT). CI ¼ confidence interval; HR ¼ hazard ratio.
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Duration of Triple Therapy and PCI Outcomes
F I G U R E 3 Kaplan-Meier Event Rates for Bleeding Outcomes
Cumulative incidence of the secondary bleeding endpoint, Bleeding Academic Research Consortium (BARC) $3 bleeding (A) and TIMI (Thrombolysis In Myocardial Infarction) major bleeding during 1 year (C) with landmark analyses at 30 days (B and D, respectively) in patients discharged on 1-month or longer duration of triple antithrombotic therapy (TAT). CI ¼ confidence interval; HR ¼ hazard ratio.
discharged on short-term TAT, and a similar propor-
TAT cessation in the 1-month treatment group.
tion of patients with HAS-BLED scores #2 were
Although it is not possible to disentangle medication-
planned to receive longer term TAT (Figure 1C). Of
related from patient-related effects in this non-
note, 3-month treatment was prescribed in more
randomized investigation, these findings likely relate
than one-half of patients in the longer duration TAT
to physician guidance, avoiding prolonged TAT in
group (i.e., shorter than the 6-month duration in ISAR-
patients at increased bleeding risk. Focusing on the
TRIPLE) (18). The maximal extent to which TAT can be
time frame between 1 and 12 months, it is reasonable
safely reduced, also in conjunction with patient- and
to assume that higher patient-specific bleeding sus-
device-specific factors, requires further investigation.
ceptibility in patients treated with 1-month TAT may
Long-term exposure to TAT has been consistently
have counterbalanced the protective effect of an
linked to higher bleeding risk compared with less
earlier transition to less intensive regimens (mostly
intensive regimens (14–16,28). In this study, shorter
OAC plus antiplatelet monotherapy). This interpre-
TAT duration was not associated with a reduction of
tation is nonetheless speculative and requires further
clinically relevant bleeding complications throughout
investigation in a prospective fashion, accounting for
1 year compared with more extended TAT treatment.
different bleeding risks in conjunction with differing
This finding held true in landmark analyses following
antithrombotic treatment durations.
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F I G U R E 4 Kaplan-Meier Event Rates for the Secondary Ischemic Endpoint
Cumulative incidence of the composite of cardiac death, myocardial infarction (MI), stroke, or definite stent thrombosis (A) and landmark analysis at 30 days (B) in patients discharged on 1-month or longer duration of triple antithrombotic therapy (TAT). CI ¼ confidence interval; HR ¼ hazard ratio.
The finding of nondiffering ischemic outcomes
and 12 months (31) or following DAPT cessation (26).
associated with 1-month TAT is reassuring but re-
Randomized trials adequately powered to assess
quires cautious interpretation, in view of the modest
ischemic outcomes, including the PIONEER AF-PCI
sample size and observational nature of this study.
(A Study Exploring Two Strategies of Rivaroxaban
Notably, patients in the longer TAT group were likely
[JNJ39039039; BAY-59-7939] and One of Oral Vitamin
at higher ischemic risk, as reflected by a higher fre-
K Antagonist in Patients With Atrial Fibrillation
quency of ACS and particularly ST-segment elevation
Who Undergo Percutaneous Coronary Intervention;
MI at baseline. In this context, the trend toward a
NCT01830543) and the REDUAL-PCI trial (Evaluation
higher MI rate in the long-TAT group within the first
of Dual Therapy With Dabigatran vs. Triple Therapy
month (i.e., during the time frame when anti-
With Warfarin in Patients With AF That Undergo a
thrombotic treatment modes did not differ between
PCI With Stenting; NCT02164864), are currently
groups) (Online Table 1) suggests a possible effect
investigating optimal combinations and durations
of patient-related factors on outcomes. However,
of antiplatelet agents, warfarin, and novel OAC
the small number of 30-day events and the non-
medications.
randomized study design limit the ability to draw
Omission of aspirin has been proposed as a means
definitive conclusions in this respect. It should also be
of mitigating the bleeding hazard of TAT (14–16). In
noted that BMS were used in 25% of patients treated
the WOEST (What Is the Optimal Antiplatelet &
with 1-month TAT, although results did not differ after
Anticoagulant Therapy in Patients With Oral Anti-
adjustment for stent type. The present findings are
coagulation and Coronary Stenting) trial, patients
in line with evidence of comparable ischemic out-
randomized to OAC plus clopidogrel versus TAT had
comes in orally anticoagulated patients when DAPT
lower rates of any bleeding but similar TIMI major
duration following PCI with DES was shortened to the
bleeding, similar ischemic events, and reduced mor-
duration generally recommended for BMS (18). Along
tality (14). A large, nationwide registry reported
the
(Zotarolimus-Eluting
higher rates of bleeding with TAT compared with
Endeavor Sprint Stent in Uncertain DES Candidates)
same
lines,
the
ZEUS
OAC, alone or in combination with antiplatelet mon-
trial showed no signal of risk in patients who were at
otherapy, without difference in thromboembolic risk
high bleeding and/or ischemic risk (including patients
(16). Although these investigations provided valuable
treated with OAC) despite shortening of DAPT to 30
insights, they compared prolonged, 1-year TAT
days after PCI with new-generation DES (29). Evidence
treatment (which is expected to increase bleeding
from nonanticoagulated patients appears to support
complications) and, in contrast to the present study,
shorter DAPT regimens following PCI with new-
assessed TAT in a binary fashion (i.e., not addressing
generation DES (30) and indicates similar risks
differing TAT durations with subsequent transi-
for stent thrombosis for DES versus BMS between 1
tion to less intensive regimens, as is currently
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Duration of Triple Therapy and PCI Outcomes
F I G U R E 5 Subgroup Analyses for the Primary and Secondary Endpoints
Stratified analyses of 1-year clinical outcomes in relation to clinical presentation, treatment with any drug-eluting stent (DES), and atrial fibrillation as main indication for oral anticoagulation. Depicted are number of first events (percentage from Kaplan-Meier estimate), and hazard ratios (HRs) (95% confidence intervals [CIs]) from Cox regressions. ACS ¼ acute coronary syndrome(s); CAD ¼ coronary artery disease; TAT ¼ triple antithrombotic therapy.
recommended). The combination of OAC plus clopi-
treatment durations pertain to prescription times
dogrel may be considered as an alternative to TAT for
at discharge, because the actual treatment duration
selected patients with high bleeding and low ischemic
was not consistently recorded. Although multivariate
risk (7); this therapeutic option could not be tested in
adjustments were performed to account for baseline
the present study.
differences, the effect of unmeasured baseline confounders cannot be excluded. The findings of the
STUDY LIMITATIONS. This study had several limita-
exploratory analyses are presented as hypothesis
tions attributable to its observational nature. First,
generating only; prospective studies are needed to
the registry was not designed to evaluate clinical
definitively address the contribution of different
outcomes in relation to TAT; however, ischemic and
antithrombotic
bleeding events were prospectively defined outcome
impact of patient-specific ischemic and bleeding risks
treatment
durations
versus
the
measures and were specifically evaluated during
on clinical outcomes. This study could not assess the
1-year follow-up. The duration of TAT was not pre-
role of less intensive antithrombotic regimens (e.g.,
defined but was individualized by physician judg-
OAC plus antiplatelet monotherapy); ongoing trials
ment; our findings nonetheless reflect real-world
are expected to address these issues. The present
practice, and treatment was tailored to individual
findings are applicable to TAT including clopidogrel,
patient risk, as is recommended in current guidelines.
because the number of patients treated with more
A notable limitation is the fact that that reported
potent P2Y 12 inhibitors was too small to allow a
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meaningful subanalysis; the impact of prasugrel as part of TAT regimens has been addressed in studies including more prasugrel-treated patients (28,32). The difference of prescribed TAT duration between groups was small; this may have limited the ability to detect differences in outcomes in relation to treatment duration.
undergoing PCI, 1-month TAT was associated with similar bleeding, ischemic, and net clinical outcomes compared with longer TAT durations throughout 1 year in this observational study. Reducing the duration of TAT to 1 month appears to be a reasonable option in patients with high bleeding risk. These findings require confirmation in prospective studies regimens
of
pre-specified
lengths
tailored to individual patient ischemic and bleeding risks. REPRINT
who require OAC who undergo PCI. Although triple therapy is recommended to be limited in duration in current consensus documents, there are few data OAC plus DAPT.
Among patients with clinical indications for OAC
TAT
WHAT IS KNOWN? TAT is indicated for patients
addressing the optimal length of the combination of
CONCLUSIONS
testing
PERSPECTIVES
WHAT IS NEW? In this observational study of 568 unselected patients undergoing PCI, we found similar ischemic events, bleeding events, and net clinical outcomes associated with abbreviated, 1-month duration versus more prolonged duration of triple therapy. These findings held true in analyses stratified for clinical presentation with stable CAD versus ACS and for interventions using DES versus BMS. WHAT IS NEXT? Data from larger, prospective studies are needed to determine clinical outcomes in relation to pre-specified triple-therapy durations
REQUESTS
AND
CORRESPONDENCE:
Dr. Lorenz Räber, Bern University Hospital, Department of Cardiology, Freiburgstrasse, Bern 3010, Switzerland.
tailored to individual patient ischemic and bleeding risks and to assess the role of novel oral anticoagulant medications in this clinical setting.
E-mail: [email protected].
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KEY WORDS anticoagulation, antiplatelet, bleeding, coronary intervention A PP END IX For supplemental tables and a figure, please see the online version of this article.
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