High Bleeding Risk

new england
The
journal of medicine
established in 1812 October 28, 2021 vol. 385 no. 18
Dual Antiplatelet Therapy after PCI in Patients

at High Bleeding Risk
M. Valgimigli, E. Frigoli, D. Heg, J. Tijssen, P. Jüni, P. Vranckx, Y. Ozaki, M.-C. Morice, B. Chevalier, Y. Onuma,
S. Windecker, P.A.L. Tonino, M. Roffi, M. Lesiak, F. Mahfoud, J. Bartunek, D. Hildick‑Smith, A. Colombo,
G. Stanković, A. Iñiguez, C. Schultz, R. Kornowski, P.J.L. Ong, M. Alasnag, A.E. Rodriguez, A. Moschovitis,
P. Laanmets, M. Donahue, S. Leonardi, and P.C. Smits, for the MASTER DAPT Investigators*
a bs t r ac t
BACKGROUND
The appropriate duration of dual antiplatelet therapy in patients at high risk for The authors’ full names, academic de-
bleeding after the implantation of a drug-eluting coronary stent remains unclear. grees, and affiliations are listed in the
Appendix. Address reprint requests to Dr.
METHODS Valgimigli at Cardiocentro Ticino Insti-
tute, Ente Ospedaliero Cantonale, Uni-
One month after they had undergone implantation of a biodegradable-polymer versità della Svizzera Italiana, Via Tesse-
sirolimus-eluting coronary stent, we randomly assigned patients at high bleeding rete 48, 6900 CH, Lugano, Switzerland,
risk to discontinue dual antiplatelet therapy immediately (abbreviated therapy) or or at marco.valgimigli@eoc.ch.
to continue it for at least 2 additional months (standard therapy). The three ranked *A complete list of the MASTER DAPT inves-
primary outcomes were net adverse clinical events (a composite of death from any tigators is provided in the Supplemen-
tary Appendix, available at NEJM.org.
cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac
or cerebral events (a composite of death from any cause, myocardial infarction, or This article was published on August 28,
2021, at NEJM.org.
stroke), and major or clinically relevant nonmajor bleeding; cumulative incidences
were assessed at 335 days. The first two outcomes were assessed for noninferior- N Engl J Med 2021;385:1643-55.
DOI: 10.1056/NEJMoa2108749
ity in the per-protocol population, and the third outcome for superiority in the Copyright © 2021 Massachusetts Medical Society.
intention-to-treat population.
CME
RESULTS at NEJM.org
Among the 4434 patients in the per-protocol population, net adverse clinical
events occurred in 165 patients (7.5%) in the abbreviated-therapy group and in 172
(7.7%) in the standard-therapy group (difference, −0.23 percentage points; 95%
confidence interval [CI], −1.80 to 1.33; P<0.001 for noninferiority). A total of 133
patients (6.1%) in the abbreviated-therapy group and 132 patients (5.9%) in the
standard-therapy group had a major adverse cardiac or cerebral event (difference,
0.11 percentage points; 95% CI, −1.29 to 1.51; P = 0.001 for noninferiority). Among
the 4579 patients in the intention-to-treat population, major or clinically relevant
nonmajor bleeding occurred in 148 patients (6.5%) in the abbreviated-therapy
group and in 211 (9.4%) in the standard-therapy group (difference, −2.82 percent-
age points; 95% CI, −4.40 to −1.24; P<0.001 for superiority).
CONCLUSIONS
One month of dual antiplatelet therapy was noninferior to the continuation of
therapy for at least 2 additional months with regard to the occurrence of net adverse
clinical events and major adverse cardiac or cerebral events; abbreviated therapy also
resulted in a lower incidence of major or clinically relevant nonmajor bleeding.
(Funded by Terumo; MASTER DAPT ClinicalTrials.gov number, NCT03023020.)
n engl j med 385;18 nejm.org October 28, 2021 1643

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Copyright © 2021 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
R
andomized trials have established provided by a medical writer and was funded by
the superiority of drug-eluting stents over the European Cardiovascular Research Institute.
bare-metal stents in patients at high The authors vouch for the accuracy and com-
bleeding risk receiving 1 month of dual anti- pleteness of the data and for the fidelity of the
platelet therapy after undergoing percutaneous trial to the protocol, available at NEJM.org.
A Quick Take is
available at coronary intervention (PCI).1-3 Nevertheless, these
NEJM.org trials were not designed to assess the appropri- Patients
ate duration of dual antiplatelet therapy after the Patients were considered to be candidates for
implantation of a drug-eluting stent. Studies of participation in the trial if they had an acute or
1 month of dual antiplatelet therapy after the chronic coronary syndrome; had undergone suc-
implantation of a drug-eluting stent have sug- cessful PCI for one or more coronary-artery
gested that this regimen may mitigate bleeding stenoses with implantation of a biodegradable-
risk without compromising safety, as compared polymer sirolimus-eluting stent (Ultimaster,
with longer durations of treatment.4-7 Some of Terumo), and no further revascularization of
these studies were nonrandomized,7 did not se- additional coronary-artery stenoses, if present,
lect patients at high bleeding risk,4-6 or included was planned8; and met one or more of the crite-
patients at low ischemic risk.4 ria for high bleeding risk (see the Supplementary
Therefore, the appropriate duration of dual Appendix). In addition, eligible patients were
antiplatelet therapy for preventing ischemic com- required to be free from adverse cardiovascular
plications, while limiting bleeding risk, in un- events (including a new acute coronary syn-
selected patients at high bleeding risk after the drome, symptomatic restenosis, stent thrombo-
implantation of a drug-eluting stent remains sis, stroke, or any revascularization resulting in
unclear. We conducted a randomized trial in- the prolonged use of dual antiplatelet therapy)
volving patients at high risk for bleeding who during the first month after the index PCI. Key
had undergone implantation of a biodegradable- exclusion criteria were the implantation of a stent
polymer sirolimus-eluting stent, in order to evalu- other than the Ultimaster stent within 6 months
ate 1 month of dual antiplatelet therapy as before the index procedure, the implantation of
compared with a longer course of dual antiplate- a bioresorbable scaffold at any time before the
let therapy with respect to clinical outcomes in- index procedure, and treatment for in-stent re-
cluding ischemic events and bleeding. stenosis or stent thrombosis. A full list of the
inclusion and exclusion criteria is provided in
the Supplementary Appendix. All the patients
Me thods
provided written informed consent.
Trial Oversight
The Management of High Bleeding Risk Patients Randomization and Follow-up
Post Bioresorbable Polymer Coated Stent Im- Patients who were free from ischemic and active
plantation with an Abbreviated versus Standard (i.e., not resolved at the time of randomization)
DAPT Regimen (MASTER DAPT) trial was an bleeding events and who adhered to a dual anti-
investigator-initiated, multicenter, randomized, platelet therapy regimen were screened for inclu-
open-label, noninferiority trial with sequential sion in the trial 30 to 44 days after the index
superiority testing. The trial was designed by procedure (defined either as a single procedure
the first and last authors and was approved by the or as the last installment of a planned staged
institutional review board at each center.8 The procedure). Patients were randomly assigned in
European Cardiovascular Research Institute acted a 1:1 ratio with the use of a central system to
as the trial sponsor and received grant support receive either open-label abbreviated dual anti-
from Terumo (see the Supplementary Appendix, platelet therapy (abbreviated-therapy group) or
available with the full text of this article at standard dual antiplatelet therapy (standard-
NEJM.org). The European Cardiovascular Re- therapy group). Randomization was concealed
search Institute and Terumo had no role in the with the use of a Web-based system. Random-
trial design; in the collection, monitoring, analy- ization sequences were computer-generated with
sis, or interpretation of the data; or in the writ- randomly selected block sizes of two, four, or six
ing of the manuscript. Editorial assistance was and stratified according to trial site, history of
1644 n engl j med 385;18 nejm.org October 28, 2021

DAPT after PCI in Patients at High Bleeding Risk
acute myocardial infarction within the past 12 myocardial infarction, or stroke; death from car-
months, and clinical indication for 12 months of diovascular or noncardiovascular causes; definite
oral anticoagulation. Follow-up visits occurred or probable stent thrombosis; and all bleeding
at 60 days (within a window of ±14 days) and events. Outcome events were adjudicated accord-
150 days (±14-day window) after randomiza- ing to definitions of the Academic Research
tion, preferably as on-site visits, and at 335 days Consortium10 and BARC by a committee whose
(±14-day window) after randomization, exclusive members were unaware of the trial-group as-
ly as an on-site visit. Follow-up data were ob- signments (see the Supplementary Appendix).
tained with a standardized questionnaire.
Statistical Analysis
Randomized Treatment The trial was designed to test hierarchically
Patients who had been randomly assigned to the whether the abbreviated dual antiplatelet regi-
abbreviated-therapy group immediately discon- men, as compared with the standard dual anti-
tinued dual antiplatelet therapy and continued platelet regimen, would be noninferior with re-
single antiplatelet therapy until the completion gard to net adverse clinical events, noninferior
of the trial, except for patients who were receiv- with regard to major adverse cardiac or cerebral
ing clinically indicated oral anticoagulation, events, and superior with regard to major or
who continued single antiplatelet therapy up to clinically relevant bleeding, as determined by the
6 months after the index procedure. Patients difference in the cumulative incidence at 335
who had been randomly assigned to the stan- days (abbreviated-therapy group minus standard-
dard-therapy group continued dual antiplatelet therapy group). The upper limit of the two-sided
therapy for at least 5 additional months (6 months 95% confidence interval for the difference in the
after the index procedure) or, for those receiving cumulative incidence had to exclude 3.6 percent-
clinically indicated oral anticoagulation, for at age points for net adverse clinical events and 2.4
least 2 additional months (3 months after the percentage points for major adverse cardiac and
index procedure) with the continuation of single cerebral events to define noninferiority and had
antiplatelet therapy thereafter. Single antiplatelet to exclude 0.0 percentage points for major or
therapy consisted of aspirin or a P2Y12 inhibitor. clinically relevant bleeding events to define su-
Antiplatelet and anticoagulant treatments were periority. These hypotheses were hierarchically
administered according to authorizations for use tested, with preservation of alpha (a one-sided
and locally approved regimens; detailed descrip- alpha of 0.025, corresponding to a two-sided alpha
tions of the two treatment regimens are provid- of 0.05).
ed in the Supplementary Appendix. We calculated that the enrollment of 4100
patients would provide the trial with 90% power
Trial Outcomes to show noninferiority with regard to net ad-
The trial protocol prespecified three ranked pri- verse clinical events under an assumed cumula-
mary outcomes: net adverse clinical events (a tive incidence of 12.0% in each group, with 80%
composite of death from any cause, myocardial power to show noninferiority with regard to
infarction, stroke, or major bleeding), major major adverse cardiac and cerebral events under
adverse cardiac or cerebral events (a composite an assumed incidence of 8.0% in each group,
of death from any cause, myocardial infarction, and with 90% power to show superiority with
or stroke), and major or clinically relevant non- regard to major or clinically relevant bleeding
major bleeding, occurring between randomiza- under an assumed incidence of 6.5% in the
tion and 335 days. Major bleeding was defined standard-therapy group and 4.2% in the abbrevi-
as a bleeding event of Bleeding Academic Re- ated-therapy group. The final sample size was
search Consortium (BARC) type 3 or 5, and increased to 4300 to account for an anticipated
major or clinically relevant nonmajor bleeding 5% of the patients withdrawing (owing to loss
was defined as a bleeding event of BARC type 2, to follow-up, withdrawal of consent, or lack of
3, or 5.9 adherence to the assigned regimen).
Secondary outcomes included the individual The primary analyses of net adverse clinical
components of the three primary outcomes; a events and major adverse cardiac and cerebral
composite of death from cardiovascular causes, events were performed in the per-protocol popu-

lation, which excluded patients who did not meet risk criteria is shown in Table S5 (mean [±SD]
the selection criteria or did not implement the number of criteria met per patient, 2.1±1.1). Of
protocol-mandated therapy within 14 days after the 4579 patients who were included in the trial,
randomization. The primary analysis of bleeding 2211 (48.3%) had undergone coronary interven-
outcomes was performed in the intention-to-treat tion for an acute coronary syndrome. Information
population, which included all the patients who on the lesion and procedural characteristics is
had undergone randomization. Differences in the provided in Tables S6 and S7.
cumulative incidences at 335 days and P values After randomization, 2250 patients (98.0%)
were calculated with the use of the Com-Nougue in the abbreviated-therapy group discontinued
method.11 Kaplan−Meier curves were created for dual antiplatelet therapy, and 2276 patients
the first two primary outcomes, and cause-spe- (99.6%) in the standard-therapy group continued
cific Kaplan−Meier curves were created for the the treatment for a median of 157 days (inter-
third primary outcome (with censoring at the quartile range, 65 to 335). The median duration
time of the competing risk event of death not of dual antiplatelet therapy from the index PCI
related to bleeding). Additional details about the was 34 days (interquartile range, 31 to 39) in the
statistical analysis are provided in the Supple- abbreviated-therapy group and 193 days (inter-
mentary Appendix. quartile range, 102 to 366) in the standard-
therapy group. After randomization, clopidogrel
was used as monotherapy in 53.9% of the pa-
R e sult s
tients in the abbreviated-therapy group and as
Enrollment and Treatment of the Patients part of dual antiplatelet therapy in 78.7% of the
From February 28, 2017, to December 5, 2019, a patients in the standard-therapy group. Medica-
total of 5204 patients (at 140 sites in 30 coun- tion use is shown in Tables S8 and S9 and Figure
tries) underwent screening; 4520 patients under- S1. Adherence to the assigned regimen was high
went screening during the 1-month period after in each group (Figs. S2 and S3).
the index procedure, of whom 202 (5.2%) with-
drew consent and 33 were lost to follow-up, and Primary Outcomes
684 underwent screening at the time of random- Complete follow-up data at 335 days were avail-
ization (Fig. 1). A total of 4579 patients (88.0%) able for 4547 patients (99.3%). A total of 32 pa-
were randomly assigned to either the abbreviated- tients (0.7%) either withdrew consent (22 patients)
therapy group (2295 patients) or the standard- or were lost to follow-up (10) and had their data
therapy group (2284 patients); the median time censored at the last contact (Fig. 1). In the per-
from the index PCI to randomization was 34 days protocol population, net adverse clinical events
in each group. A screening log for a sample sub- occurred in 165 patients (7.5%) in the abbreviated-
group of trial candidates showed that, of 2847 therapy group and in 172 (7.7%) in the standard-
patients who underwent screening, 109 (3.8%) therapy group (hazard ratio, 0.97; 95% confi-
were enrolled in the trial (Table S1 in the Supple- dence interval [CI], 0.78 to 1.20), for a difference
mentary Appendix). Details regarding the 625 in risk of −0.23 percentage points (95% CI,
patients who provided written informed consent −1.80 to 1.33; P<0.001 for noninferiority). In
but did not undergo randomization and regard- the same population, 133 patients (6.1%) in the
ing the patients in the per-protocol population abbreviated-therapy group and 132 patients
are provided in Tables S2 through S4. (5.9%) in the standard-therapy group had a ma-
The characteristics of the patients at baseline jor adverse cardiac and cerebral event (hazard
and their clinical presentation are shown in Ta- ratio, 1.02; 95% CI, 0.80 to 1.30), for a difference
ble 1. Overall, the mean age of the patients was in risk of 0.11 percentage points (95% CI, −1.29 to
76.0 years, 69.3% of the patients were men, 1.51; P = 0.001 for noninferiority). In the inten-
33.6% had diabetes, 19.1% had chronic kidney tion-to-treat population, the incidence of major
disease, 18.9% had heart failure, 12.4% had pre- or clinically relevant nonmajor bleeding was
viously had a cerebrovascular event, and 10.6% lower among patients in the abbreviated-therapy
had peripheral vascular disease; 36.4% of the group than among those in the standard-therapy
patients were receiving concomitant oral antico- group (148 patients [6.5%] vs. 211 [9.4%]; haz-
agulation. The distribution of the high-bleeding- ard ratio, 0.68; 95% CI, 0.55 to 0.84), for a dif-

4520 Patients provided informed

consent before 1-mo visit
267 Were excluded

5 Were not eligible
27 Died before 1 mo
33 Were lost to follow-up or did not attend
1-mo visit
202 Withdrew consent
684 Patients provided informed

4937 Were assessed for eligibility at 1 mo
consent at 1-mo visit
358 Were excluded

304 Were not eligible
54 Had medical reason
4579 Underwent randomization
2295 Were assigned to abbreviated DAPT 2284 Were assigned to standard DAPT
43 Did not start assigned regimen 8 Did not start assigned regimen
48 Did not meet eligibility criteria after internal 46 Did not meet eligibility criteria after internal
review review
2204 Were included in the per-protocol population 2230 Were included in the per-protocol population
2 Were lost to follow-up 8 Were lost to follow-up

13 Withdrew consent 9 Withdrew consent
2205 Were alive 2186 Were alive

2018 Were adhering to assigned regimen 2113 Were adhering to assigned regimen
187 Were not adhering to assigned regimen 73 Were not adhering to assigned regimen
75 Died 81 Died
69 Had been adhering to assigned regimen 75 Had been adhering to assigned regimen
6 Had not been adhering to assigned regimen 6 Had not been adhering to assigned regimen
2295 Were included in the intention-to-treat population 2284 Were included in the intention-to-treat population
15 Had data censored at last contact 17 Had data censored at last contact
2204 Were included in the per-protocol population 2230 Were included in the per-protocol population
10 Had data censored at last contact 16 Had data censored at last contact
Figure 1. Randomization, Treatment, and Follow-up of the Patients.

Patients provided written informed consent either during the interval between the index percutaneous coronary in-
tervention and the 1-month randomization visit or at the 1-month visit. Patients who provided consent before the
1-month visit could later be excluded (e.g., for death or withdrawal of consent), whereas those who provided consent
at the 1-month visit were all included in the trial. Patients who did not start the assigned antiplatelet regimen were
those who did not start the regimen within 14 days after randomization or who started a nonallowed regimen owing
to an event occurring within 14 days after randomization. Patients who are indicated as receiving the assigned anti-
platelet regimen were those who were noted as adhering to the regimen on day 335; if the information was not re-
corded on day 335, the latest available information on adherence was used. In the per-protocol population, one pa-
tient in the abbreviated-therapy group was lost to follow-up and nine withdrew consent; in the standard-therapy
group, seven patients were lost to follow-up and nine withdrew consent. DAPT denotes dual antiplatelet therapy.
ference in risk of −2.82 percentage points (95% Secondary Outcomes

CI, −4.40 to –1.24; P<0.001 for superiority). De- The Kaplan–Meier cumulative incidence of death
tails are shown in Table 2 and Figure 2. from any cause was similar in the abbreviated-

Table 1. Characteristics and Clinical Presentation of the Patients at Baseline.*
Abbreviated Dual Standard Dual

Antiplatelet Therapy Antiplatelet Therapy
Characteristic (N = 2295) (N = 2284)
Age — yr 76.1±8.7 76.0±8.8
Male sex — no. (%) 1590 (69.3) 1581 (69.2)
Body-mass index† 27.25±4.68 27.44±4.74
Family history of coronary artery disease — no. (%) 556 (24.2) 553 (24.2)
Arterial hypertension — no. (%) 1766 (76.9) 1787 (78.2)
Diabetes mellitus — no. (%) 754 (32.9) 784 (34.3)
Hyperlipidemia — no. (%) 1542 (67.2) 1555 (68.1)
Smoking — no./total no. (%)
Previous 874/2290 (38.2) 854/2276 (37.5)
Current 230/2290 (10.0) 184/2276 (8.1)
Peripheral vascular disease — no. (%)‡ 243 (10.6) 242 (10.6)
Carotid artery disease — no. (%) 120 (5.2) 144 (6.3)
Heart failure — no. (%) 429 (18.7) 438 (19.2)
Left ventricular ejection fraction — %§ 53.48±11.44 52.96±11.77
Previous myocardial infarction — no. (%) 434 (18.9) 430 (18.8)
Previous percutaneous coronary intervention — no. (%) 594 (25.9) 594 (26.0)
Previous cerebrovascular event — no. (%) 268 (11.7) 302 (13.2)
Previous coronary-artery bypass grafting — no. (%) 170 (7.4) 171 (7.5)
Chronic pulmonary disease — no. (%) 255 (11.1) 283 (12.4)
Chronic kidney disease — no. (%)¶ 418 (18.2) 458 (20.1)
Liver disease — no. (%) 29 (1.3) 32 (1.4)
Atrial fibrillation — no. (%) 770 (33.6) 720 (31.5)
Oral anticoagulant — no. (%)‖ 849 (37.0) 820 (35.9)
PRECISE-DAPT score** 26.81±10.91 26.71±11.06
Previous bleeding — no. (%) 165 (7.2) 155 (6.8)
Hemoglobin — g/liter 13.23±1.78 13.20±1.79
White-cell count — ×10−9/liter†† 8.29±11.44 8.05±3.40
Creatinine clearance — ml/min/1.73 m ‡‡ 2
70.72±23.99 71.00±24.10
Clinical presentation
Stable angina — no. (%) 922 (40.2) 927 (40.6)
Silent ischemia — no. (%) 245 (10.7) 274 (12.0)
Non–ST-elevation myocardial infarction — no. (%) 595 (25.9) 558 (24.4)
ST-elevation myocardial infarction — no. (%) 273 (11.9) 265 (11.6)
Unstable angina — no. (%) 260 (11.3) 260 (11.4)
Myocardial infarction of Killip class II, III, or IV — no. (%) 252 (11.0) 254 (11.1)
Cardiac arrest — no. (%) 26 (1.1) 32 (1.4)
* Plus–minus values are means ±SD. Data on race and ethnic group are not reported because of restrictions on obtain-
ing this information from patients recruited in France.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Peripheral vascular disease was defined as intermittent claudication, peripheral-artery bypass for insufficiency, gan-
grene, acute arterial insufficiency, untreated aneurysm (≥6 cm in diameter), an ankle brachial index of no more than
0.90, or aortic plaque.
§ Data on the left ventricular ejection fraction were available for 2169 patients in the abbreviated-therapy group and for
2128 in the standard-therapy group.

Table 1. (Continued.)
¶ Chronic kidney disease was defined as kidney damage (pathologic abnormalities or markers of damage, including ab-
normalities in blood or urine tests or imaging studies) or an estimated glomerular filtration rate of less than 60 ml
per minute per 1.73 m2 of body-surface area for at least 3 months.
‖ Oral anticoagulants were a vitamin K antagonist or a non–vitamin K antagonist oral anticoagulant.
** Scores on the PRECISE-DAPT, in which the components are the patient’s age, previous bleeding, hemoglobin level,
white-cell count, and creatinine clearance, range from 0 to 100. Patients with a score of 25 or higher are at high risk
for bleeding.
†† The white-cell count was calculated at screening visit. One patient in the standard-therapy group had a PRECISE-DAPT
score calculated without the white-cell count.
‡‡ The creatinine clearance was calculated with the use of the Modification of Diet in Renal Disease method.
therapy group and the standard-therapy group or chronic coronary syndrome, the discontinua-
(3.3% and 3.6%, respectively), as were the cumu- tion of dual antiplatelet therapy at a median of
lative incidences of myocardial infarction (2.7% 34 days after PCI was noninferior to the con-
and 2.2%, respectively) and definite or probable tinuation of dual antiplatelet therapy for a median
stent thrombosis (0.6% and 0.4%) (Table 2). A duration of 193 days with regard to net adverse
cerebrovascular event occurred in 17 patients clinical events and major adverse cardiac or cere-
(0.8%) in the abbreviated-therapy group and in bral events and was superior with regard to
32 (1.4%) in the standard-therapy group. Stroke major or clinically relevant nonmajor bleeding.
occurred in 12 patients (0.5%) in the abbreviated- Secondary efficacy outcomes were generally simi-
therapy group and in 23 (1.0%) in the standard- lar in the two groups. Treatment effects with
therapy group; hemorrhagic stroke occurred in regard to the three primary outcomes were con-
1 and 5 patients, respectively. sistent across subgroups.
The cumulative incidence of BARC type 2 The incidence of major or clinically relevant
bleeding was lower in the abbreviated-therapy nonmajor bleeding in the intention-to-treat pop-
group than in the standard-therapy group (4.5% ulation (the third primary outcome) was 6.5% in
vs. 6.8%; difference, −2.25 percentage points; the abbreviated-therapy group and 9.4% in the
95% CI, −3.59 to −0.90), but the cumulative in- standard-therapy group (difference, −2.82 per-
cidence of bleeding of type 3, 4, or 5 was similar centage points). The lower risk of bleeding in the
in the two groups (2.3% and 2.6%, respectively). abbreviated-therapy group was mainly due to the
Fatal bleeding (BARC type 5) occurred in 2 pa- lower incidence of clinically relevant nonmajor
tients (0.1%) in the abbreviated-therapy group bleeding events (BARC type 2) in this group than
and in 8 (0.4%) in the standard-therapy group in the standard-therapy group (4.5% vs. 6.8%).
(Table 2). We recruited patients with a high bleeding risk
regardless of clinical presentation and did not
Additional Analyses restrict the number, type, or location of target
Sensitivity analyses for noninferiority testing in coronary lesions, provided that the lesions had
the intention-to-treat population and for superi- been uniformly treated with a biodegradable-
ority testing in the per-protocol population polymer sirolimus-eluting stent and were not due
yielded consistent results for the primary and to in-stent restenosis or stent thrombosis. Patients
secondary outcomes (Table 2 and Figs. S4 through were screened primarily at the time of stent im-
S6). The effects of abbreviated therapy as com- plantation, and only a few of the potentially eli-
pared with standard dual antiplatelet therapy on gible patients (5.2%) withdrew before or at ran-
the incidences of the three primary outcomes domization. Our trial population differs from
were largely consistent across subgroups (Figs. S7 those in studies that excluded patients with
through S9). acute coronary syndrome12 and that limited the
number, location, or complexity of treated le-
sions.12,13 Our results therefore inform treatment
Discussion
decisions regarding dual antiplatelet therapy at
Among patients at high risk for bleeding who 1 month after coronary intervention in patients
had undergone implantation with a biodegrad- at high risk for bleeding who do not have post-
able-polymer sirolimus-eluting stent for an acute procedural ischemic events, including patients

1650
Table 2. Composite Primary Outcomes and Secondary Outcomes in the Per-Protocol and Intention-to-Treat Populations.*
Outcome Per-Protocol Population Intention-to-Treat Population
Abbreviated Standard Risk Abbreviated Standard Risk

DAPT DAPT Hazard Ratio Difference DAPT DAPT Hazard Ratio Difference
(N = 2204) (N = 2230) (95% CI) (95% CI) (N = 2295) (N = 2284) (95% CI) (95% CI)
number (percent) percentage points number (percent) percentage points

Composite primary outcomes†
The
Net adverse clinical events 165 (7.5) 172 (7.7) 0.97 (0.78 to 1.20) −0.23 172 (7.5) 182 (8.0) 0.94 (0.76 to 1.15) −0.48
(−1.80 to 1.33) (−2.03 to 1.08)
Major adverse cardiac or cerebral 133 (6.1) 132 (5.9) 1.02 (0.80 to 1.30) 0.11 138 (6.0) 138 (6.1) 0.99 (0.78 to 1.26) −0.03
events (−1.29 to 1.51) (−1.42 to 1.35)
Major or nonmajor clinically rel- 140 (6.4) 203 (9.2) 0.68 (0.55 to 0.85) −2.78 148 (6.5) 211 (9.4) 0.68 (0.55 to 0.84)‡ −2.82
evant bleeding (−4.37 to −1.20) (−4.40 to −1.24)
n engl j med 385;18

Secondary outcomes
Death from cardiovascular causes, 100 (4.6) 97 (4.4) 1.04 (0.79 to 1.38) — 103 (4.5) 102 (4.5) 1.00 (0.76 to 1.32) —
myocardial infarction,
or stroke
nejm.org
Death 72 (3.3) 79 (3.6) 0.92 (0.67 to 1.26) — 75 (3.3) 81 (3.6) 0.92 (0.67 to 1.26) —
n e w e ng l a n d j o u r na l
Death from cardiovascular 36 (1.7) 43 (2.0) 0.84 (0.54 to 1.31) — 37 (1.6) 44 (2.0) 0.83 (0.54 to 1.29) —

of
causes
Death from noncardiovascular 27 (1.2) 27 (1.2) 1.01 (0.59 to 1.72) — 29 (1.3) 28 (1.2) 1.03 (0.61 to 1.73) —
causes
October 28, 2021

Stroke or transient ischemic attack 16 (0.7) 31 (1.4) 0.52 (0.28 to 0.95) — 17 (0.8) 32 (1.4) 0.53 (0.29 to 0.95) —

m e dic i n e
Stroke 11 (0.5) 22 (1.0) 0.50 (0.24 to 1.04) — 12 (0.5) 23 (1.0) 0.52 (0.26 to 1.04) —
Ischemic stroke 10 (0.5) 17 (0.8) — — 11 (0.5) 18 (0.8) — —
Hemorrhagic stroke 1 (<0.1) 4 (0.2) — — 1 (<0.1) 5 (0.2) — —
Myocardial infarction 59 (2.7) 46 (2.1) 1.30 (0.88 to 1.91) — 60 (2.7) 49 (2.2) 1.22 (0.84 to 1.78) —
Definite or probable stent throm- 14 (0.6) 8 (0.4) 1.77 (0.74 to 4.22) — 14 (0.6) 9 (0.4) 1.55 (0.67 to 3.57) —
bosis
Definite 11 (0.5) 6 (0.3) 1.85 (0.69 to 5.01) — 11 (0.5) 7 (0.3) 1.56 (0.61 to 4.03) —
Probable 3 (0.1) 2 (0.1) — — 3 (0.1) 2 (0.1) — —
Outcome Per-Protocol Population Intention-to-Treat Population
Abbreviated Standard Risk Abbreviated Standard Risk

DAPT DAPT Hazard Ratio Difference DAPT DAPT Hazard Ratio Difference
(N = 2204) (N = 2230) (95% CI) (95% CI) (N = 2295) (N = 2284) (95% CI) (95% CI)
number (percent) percentage points number (percent) percentage points
Bleeding
BARC type
Type 1 to 5 190 (8.7) 291 (13.2) 0.64 (0.53 to 0.77) — 202 (8.9) 304 (13.5) 0.64 (0.54 to 0.76) —
Type 2 97 (4.5) 150 (6.8) — — 102 (4.5) 152 (6.8) — —
Type 3 to 5 49 (2.3) 54 (2.5) — — 53 (2.3) 59 (2.6) — —
Type 4 0 0 — — 0 0 — —
Type 5 2 (0.1) 7 (0.3) — — 2 (0.1) 8 (0.4) — —
TIMI minor or major bleeding 38 (1.8) 44 (2.0) 0.87 (0.56 to 1.34) — 41 (1.8) 48 (2.1) 0.85 (0.56 to 1.28) —
event§
Minor 15 (0.7) 20 (0.9) — — 16 (0.7) 21 (0.9) — —
Major 23 (1.1) 24 (1.1) — — 25 (1.1) 27 (1.2) — —
GUSTO moderate or severe 44 (2.0) 46 (2.1) 0.96 (0.64 to 1.46) — 48 (2.1) 51 (2.3) 0.93 (0.63 to 1.38) —
bleeding event¶
Moderate bleeding event 36 (1.7) 35 (1.6) — — 40 (1.8) 38 (1.7) — —
n engl j med 385;18

Severe bleeding event 8 (0.4) 12 (0.6) — — 8 (0.4) 14 (0.6) — —
* The per-protocol population excluded patients who did not fulfill the selection criteria or did not implement protocol-mandated therapy within 14 days after randomization. The
nejm.org
intention-to-treat population included all the patients who underwent randomization. Percentages were calculated as Kaplan–Meier estimates of the cumulative incidence at 335 days.
Hazard ratios are shown for the primary outcomes and for principal secondary outcomes. The widths of the 95% confidence intervals for secondary outcomes were not adjusted for
multiple comparisons and should not therefore be used for inference about treatment effects. DAPT denotes dual antiplatelet therapy.
† The composite primary outcomes are listed in order of the prespecified hierarchical testing. The first primary outcome of net adverse clinical events (a composite of death from any
cause, myocardial infarction, stroke, or major bleeding, defined as Bleeding Academic Research Consortium [BARC] type 3 or 5) and the second primary outcome of major adverse
cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke) were assessed in the per-protocol population. The third primary outcome of major or
nonmajor clinically relevant bleeding (defined as bleeding of BARC type 2, 3, or 5) was assessed in the intention-to-treat population.

October 28, 2021
‡ Although the Cox proportional-hazards ratio is reported for the outcome of major or nonmajor clinically relevant bleeding, it should be noted that this outcome violated the proportion-
al-hazards assumption. The Cox hazard ratio is therefore provided for descriptive purposes only. In contrast, the calculation of the risk difference (estimated difference in cumulative
incidence) was made with the Com-Nougue method,11 which does not rely on the proportional-hazards assumption. For the other two primary end points, the proportional-hazards as-
sumption was met.

§ Thrombolysis in Myocardial Infarction (TIMI) minor bleeding was defined as an observed decrease of at least 3 g per deciliter in the hemoglobin concentration or a decrease of at least
10 percentage points in the hematocrit. TIMI major bleeding was defined as an intracranial hemorrhage, a decrease of at least 5 g per deciliter in the hemoglobin concentration, or an

absolute decrease of at least 15 percentage points in the hematocrit.
¶ Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate bleeding was defined as bleeding that led to blood transfusion but did not result in hemodynamic
compromise. GUSTO severe or life-threatening bleeding was defined as either intracranial hemorrhage or bleeding that caused hemodynamic compromise and led to intervention.
1651
A Net Adverse Clinical Events

10 Difference in cumulative incidence,
100 −0.23 percentage points (95% CI, −1.80 to 1.33)
90 P<0.001 for noninferiority 7.7
8
Cumulative Incidence (%)

80 Standard DAPT 7.5
70 6
Abbreviated DAPT
60
4
50
40 2
30
20 0
0 30 60 90 120 150 180 210 240 270 300 335
10
0
0 30 60 90 120 150 180 210 240 270 300 335
Days since Randomization
No. at Risk
Standard DAPT 2230 2203 2188 2169 2155 2137 2118 2102 2081 2068 2052 2041
Abbreviated DAPT 2204 2184 2173 2153 2138 2144 2101 2091 2070 2056 2044 2027
B Major Adverse Cardiac or Cerebral Events

10 Difference in cumulative incidence,
100 0.11 percentage points (95% CI, −1.29 to 1.51)
90 P=0.001 for noninferiority
8
Abbreviated DAPT
80 6.1
70 6
Standard DAPT 5.9
60
4
50
40 2
30
20 0
0 30 60 90 120 150 180 210 240 270 300 335
10
0
0 30 60 90 120 150 180 210 240 270 300 335
No. at Risk
Standard DAPT 2230 2218 2207 2192 2176 2165 2149 2134 2113 2102 2090 2081
C Major or Clinically Relevant Nonmajor Bleeding

10 Difference in cumulative incidence, 9.4
100 −2.82 percentage points (95% CI, −4.40 to −1.24)
90 P<0.001 for superiority
8 Standard DAPT
80 6.5
70 6
60 Abbreviated DAPT
4
50
40 2
30
20 0
0 30 60 90 120 150 180 210 240 270 300 335
10
0
0 30 60 90 120 150 180 210 240 270 300 335
No. at Risk
Standard DAPT 2284 2220 2186 2166 2147 2122 2094 2077 2060 2035 2015 1999

Figure 2 (facing page). Cumulative Incidence of Three of clopidogrel therapy with 6 months of clopido-
Primary Composite Outcomes at 335 Days. grel therapy in 614 patients receiving oral anti-
The three ranked primary outcomes were a composite coagulation who were also receiving aspirin after
of death from any cause, myocardial infarction, stroke, the implantation of a drug-eluting stent, showed
or major bleeding (net adverse clinical events), which no significant difference between the two treat-
was assessed in the per-protocol population (Panel A);
ment strategies with regard to a composite out-
a composite of death from any cause, myocardial infarc-
tion, or stroke (major adverse cardiac or cerebral events), come of death, myocardial infarction, stroke,
which was assessed in the per-protocol population (Panel stent thrombosis, or major bleeding.16
B); and major or clinically relevant nonmajor bleeding, Some limitations of our trial should be con-
which was assessed in the intention-to-treat population sidered. Although the exclusion criteria were
(Panel C). The per-protocol population excluded patients
intended to be minimal, limited screening-log
who did not fulfill the selection criteria or did not imple-
ment protocol-mandated therapy within 14 days after data suggested that approximately 4% of the
randomization. The intention-to-treat population in- patients who underwent screening (representing
cluded all the patients who underwent randomization. 21.5% of the eligible patients) were enrolled.
Insets show the same data on enlarged y axes. Treatments were open-label, which reflects the
impossibility of masking three oral P2Y12 inhibi-
tors and aspirin in a treatment-strategy trial.
with clinical or angiographic features indicating The duration of dual antiplatelet therapy was
a high ischemic risk. heterogeneous in the standard-therapy group.
The choices of the type of P2Y12 inhibitor for The type of monotherapy after the discontinua-
dual antiplatelet therapy and the type of mono- tion of dual antiplatelet therapy in the abbreviated-
therapy after the discontinuation of dual anti- therapy group also varied. The duration of dual
platelet therapy were at the discretion of the in- antiplatelet therapy in the two trial groups was
vestigator. Clopidogrel was the most frequently longer than is now recommended in patients
used P2Y12 inhibitor in the standard-therapy group receiving oral anticoagulation.17,18 However, a very
and was the most frequently used monotherapy short duration of triple antithrombotic therapy is
in the abbreviated-therapy group at the time of associated with higher rates of ischemic events
randomization and thereafter. This finding is than longer treatment.14
consistent with those of previous trials that Our trial included patients at high bleeding
exclusively enrolled patients at high bleeding risk who had undergone implantation of a bio-
risk2,3,14 and is consistent with guidelines.15 degradable-polymer sirolimus-eluting stent; con-
Two trials have compared 1 month of dual sequently, our results may not extend to patients
antiplatelet therapy with at least 12 months of who are not at high bleeding risk or who receive
dual antiplatelet therapy after PCI with drug- other stent types. Patients with in-stent resteno-
eluting stents.4,6 The GLOBAL LEADERS trial sis or stent thrombosis were ineligible for this
showed that 1 month of dual antiplatelet therapy trial. The incidences of net adverse clinical events
followed by ticagrelor monotherapy for an addi- and major adverse cardiac and cerebral events
tional 23 months was not associated with lower were lower than expected, and noninferiority
all-cause mortality or with a lower incidence of margins were wide; therefore, a modest increase
new Q-wave myocardial infarction than 12 months in the incidence of such events cannot be ruled
of dual antiplatelet therapy followed by aspirin out with this duration of abbreviated therapy.
monotherapy for an additional 12 months.6 In In this trial involving patients at high risk for
the STOPDAPT-2 trial, 1 month of dual anti- bleeding who had undergone implantation of a
platelet therapy followed by clopidogrel mono- biodegradable-polymer sirolimus-eluting stent,
therapy was associated with a lower risk of a the discontinuation of dual antiplatelet therapy
composite of cardiovascular and bleeding events at a median of 34 days after PCI was noninferior
than 12 months of dual antiplatelet therapy.4 to the continuation of treatment for a median
However, patients in that trial were at low risk duration of 193 days with regard to the inci-
for ischemic events. In both these trials, patients dence of net adverse clinical events and major
were enrolled immediately after the PCI, and adverse cardiac or cerebral events and was as-
those at high risk for bleeding were not selected. sociated with a lower incidence of major or
The ISAR-TRIPLE trial, which compared 6 weeks clinically relevant nonmajor bleeding.

Supported by Terumo. We thank Sophie Rushton-Smith, of MedLink Healthcare

Disclosure forms provided by the authors are available with Communications, funded by the European Cardiovascular
the full text of this article at NEJM.org. Research Institute, for providing editorial assistance with an
A data sharing statement provided by the authors is available earlier version of the manuscript.
with the full text of this article at NEJM.org.
Appendix
The authors’ full names and academic degrees are as follows: Marco Valgimigli, M.D., Ph.D., Enrico Frigoli, M.D., Dik Heg, Ph.D., Jan
Tijssen, Ph.D., Peter Jüni, M.D., Pascal Vranckx, M.D., Ph.D., Yukio Ozaki, M.D., Ph.D., Marie‑Claude Morice, M.D., Bernard Chevalier,
M.D., Yoshinobu Onuma, M.D., Ph.D., Stephan Windecker, M.D., Pim A.L. Tonino, M.D., Marco Roffi, M.D., Maciej Lesiak, M.D.,
Felix Mahfoud, M.D., Jozef Bartunek, M.D., Ph.D., David Hildick‑Smith, M.D., Antonio Colombo, M.D., Goran Stanković, M.D., Ph.D.,
Andrés Iñiguez, M.D., Ph.D., Carl Schultz, M.D., Ph.D., Ran Kornowski, M.D., Paul J.L. Ong, M.D., Ph.D., Mirvat Alasnag, M.D., Ph.D.,
Alfredo E. Rodriguez, M.D., Ph.D., Aris Moschovitis, M.D., Peep Laanmets, M.D., Michael Donahue, M.D., Sergio Leonardi, M.D., and
Pieter C. Smits, M.D., Ph.D.
The authors’ affiliations are as follows: the Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Università della Svizzera Italiana,
Lugano (M.V.), CTU Bern, University of Bern (E.F., D.H.), and the Department of Cardiology, Bern University Hospital (S.W.), Bern,
the Division of Cardiology, Geneva University Hospitals, Geneva (M.R.), and HerzZentrum Hirslanden Zürich, Zurich (A.M.) — all in
Switzerland; the Department of Cardiology, Amsterdam University Medical Centers, Amsterdam (J.T.), European Cardiovascular Re-
search Institute (J.T.), and the Department of Cardiology, Maasstad Hospital (P.C.S.), Rotterdam, and the Department of Cardiology,
Catharina Hospital, Eindhoven (P.A.L.T.) — all in the Netherlands; the University of Toronto, Applied Health Research Centre, Li Ka
Shing Knowledge Institute, St. Michael’s Hospital, Toronto (P.J.); the Department of Cardiology and Critical Care Medicine, Hartcen-
trum Hasselt, Jessa Ziekenhuis, and the Faculty of Medicine and Life Sciences, Hasselt University, Hasselt (P.V.), and the Cardiovascular
Center, OLV Hospital, Aalst (J.B.) — all in Belgium; the Department of Cardiology, School of Medicine, Fujita Health University, Toyo-
ake, Japan (Y. Ozaki); the Cardiovascular European Research Center (M.-C.M.), and Ramsay Générale de Santé, Interventional Cardiol-
ogy Department, Institut Cardiovasculaire Paris Sud (B.C.) — both in Massy, France; the National University of Ireland, Galway (Y.
Onuma); the First Department of Cardiology, University of Medical Sciences, Poznan, Poland (M.L.); the Department of Internal Medi-
cine III–Cardiology, Angiology, and Intensive Care Medicine, Saarland University, Homburg, Germany (F.M.); Brighton and Sussex
University Hospitals NHS Trust, Brighton, United Kingdom (D.H.-S.); the Unit of Cardiovascular Interventions, IRCCS San Raffaele
Scientific Institute, Milan (A.C.), the Interventional Cardiology Unit, Policlinico Casilino, Rome (M.D.), and the University of Pavia,
Fondazione IRCCS Policlinico San Matteo, Pavia (S.L.) — all in Italy; the Department of Cardiology, Clinical Center of Serbia, and the
Faculty of Medicine, University of Belgrade, Belgrade, Serbia (G.S.); Hospital Alvaro Cunqueiro, Vigo, Spain (A.I.); the Department of
Cardiology, Royal Perth Hospital Campus, University of Western Australia, Perth, Australia (C.S.); Rabin Medical Center, Sackler School
of Medicine, Tel Aviv University, Tel Aviv, Israel (R.K.); Tan Tock Seng Hospital, Singapore, Singapore (P.J.L.O.); the Department of
Cardiology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia (M.A.); Cardiac Unit Otamendi Hospital, Buenos Aires School of
Medicine Cardiovascular Research Center (A.E.R.); and North Estonia Medical Center Foundation, Tallinn, Estonia (P.L.).
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new england

Dual Antiplatelet Therapy after PCI in Patients

n engl j med 385;18 nejm.org October 28, 2021 1643

1644 n engl j med 385;18 nejm.org October 28, 2021

The New England Journal of Medicine

n engl j med 385;18 nejm.org October 28, 2021 1645

1646 n engl j med 385;18 nejm.org October 28, 2021

The New England Journal of Medicine

4520 Patients provided informed

267 Were excluded

684 Patients provided informed

358 Were excluded

4579 Underwent randomization

2 Were lost to follow-up 8 Were lost to follow-up

2205 Were alive 2186 Were alive

Figure 1. Randomization, Treatment, and Follow-up of the Patients.

ference in risk of −2.82 percentage points (95% Secondary Outcomes

n engl j med 385;18 nejm.org October 28, 2021 1647

Table 1. Characteristics and Clinical Presentation of the Patients at Baseline.*

Abbreviated Dual Standard Dual

1648 n engl j med 385;18 nejm.org October 28, 2021

The New England Journal of Medicine

n engl j med 385;18 nejm.org October 28, 2021 1649

Outcome Per-Protocol Population Intention-to-Treat Population

Abbreviated Standard Risk Abbreviated Standard Risk

number (percent) percentage points number (percent) percentage points

n engl j med 385;18

The New England Journal of Medicine

October 28, 2021

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

Abbreviated Standard Risk Abbreviated Standard Risk

number (percent) percentage points number (percent) percentage points

n engl j med 385;18

The New England Journal of Medicine

sumption was met.

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

A Net Adverse Clinical Events

Cumulative Incidence (%)

B Major Adverse Cardiac or Cerebral Events

C Major or Clinically Relevant Nonmajor Bleeding

1652 n engl j med 385;18 nejm.org October 28, 2021

The New England Journal of Medicine

n engl j med 385;18 nejm.org October 28, 2021 1653

Supported by Terumo. We thank Sophie Rushton-Smith, of MedLink Healthcare

1654 n engl j med 385;18 nejm.org October 28, 2021

The New England Journal of Medicine

receive immediate notification when an article

To be notified by email when Journal articles

n engl j med 385;18 nejm.org October 28, 2021 1655

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