Dual Antiplatelet Therapy for 6 Versus 18 Months After Biodegradable Polymer Drug-Eluting Stent Implantation

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 10, NO. 12, 2017

ª 2017 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2017.04.019

CORONARY

Dual Antiplatelet Therapy for 6 Versus 18 Months After Biodegradable Polymer Drug-Eluting Stent Implantation Masato Nakamura, MD, PHD,a Raisuke Iijima, MD, PHD,a Junya Ako, MD, PHD,b Toshiro Shinke, MD, PHD,c Hisayuki Okada, MD, PHD,d Yoshiaki Ito, MD, PHD,e Kenji Ando, MD,f Hitoshi Anzai, MD, PHD,g Hiroyuki Tanaka, MD, PHD,h Yasunori Ueda, MD, PHD,i Shin Takiuchi, MD, PHD,j Yasunori Nishida, MD,k Hiroshi Ohira, MD,l Katsuhiro Kawaguchi, MD, PHD,m Makoto Kadotani, MD, PHD,n Hiroyuki Niinuma, MD, PHD,o Kazuto Omiya, MD, PHD,p Takashi Morita, MD, PHD,q Kan Zen, MD, PHD,r Yoshinori Yasaka, MD, PHD,s Kenji Inoue, MD, PHD,t Sugao Ishiwata, MD, PHD,u Masahiko Ochiai, MD, PHD,v Toshimitsu Hamasaki, MSC, PHD,w Hiroyoshi Yokoi, MD,x on behalf of the NIPPON Investigators

ABSTRACT OBJECTIVES The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short-term versus long-term dual antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating. BACKGROUND The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear. METHODS The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1:1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months. RESULTS NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval [CI]: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of
2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short-term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43). CONCLUSIONS Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227) (J Am Coll Cardiol Intv 2017;10:1189–98) © 2017 Published by Elsevier on behalf of the American College of Cardiology Foundation.

From the aDivision of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan; bDepartment of Cardiovascular Medicine, Kitasato University Hospital, Sagamihara, Japan; cDivision of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; dDepartment of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan; e

Division of Cardiology, Saiseikai Yokohama-City Eastern Hospital, Yokohama, Japan; fDepartment of Cardiology, Kokura Memorial

Hospital, Kitakyushu, Japan; gCardiology Department, Ota Memorial Hospital, Ota, Japan; hDepartment of Cardiology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan; iCardiovascular Division, National Hospital Organization Osaka National Hospital, Osaka, Japan; jDepartment of Cardiology, Higashi Takarazuka Satoh Hospital, Takarazuka, Japan; kDepartment of Cardiovascular Medicine, Takai Hospital, Nara, Japan; lDepartment of Cardiology, Edogawa Hospital, Tokyo, Japan; mDepartment of

1190

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

Short-Term Versus Long-Term DAPT After Nobori Stenting

T

ABBREVIATIONS AND ACRONYMS BARC = Bleeding Academic Research Consortium

he indications for use of drug-

Dual Antiplatelet Therapy as Appropriate Duration)

eluting stents (DES) in patients

study was a prospective, multicenter, randomized

with atherosclerotic coronary artery

controlled trial (RCT) that was designed to compare

disease have been expanded due to the lower

the net clinical benefit of short-term versus long-

restenosis rates achieved with these stents.

term DAPT on the basis of assessment of efficacy

However, soon after the introduction of

and safety. All patients in this trial received the

therapy

DES into real-world practice, the new clinical

Nobori stent (Terumo, Tokyo, Japan), a promising

DES = drug-eluting stent(s)

problem of “very late stent thrombosis” was

DES for reducing the long-term risk of stent throm-

discovered, and the association between the

bosis with a biodegradable abluminal coating. This

risk of stent thrombosis and cessation of

was a RCT comparing different DAPT regimens after

dual antiplatelet therapy (DAPT) became a

implantation of a stent with a biodegradable ablumi-

topic of discussion (1–3). It was initially re-

nal coating.

CI = confidential interval DAPT = dual antiplatelet

HR = hazard ratio ITT = intention to treat MI = myocardial infarction NACCE = net adverse clinical

ported that extending the duration of DAPT

and cerebrovascular event(s)

might increase the risk of bleeding complica-

PCI = percutaneous coronary

METHODS

tions without reducing cardiovascular events

intervention

PH = proportional hazard RCT = randomized controlled trial

(4), leading to the strategy of performing

The NIPPON study was a prospective RCT that

short-term DAPT after DES implantation.

compared 6 months of DAPT (short-term DAPT) and

Other studies were subsequently conducted

18 months of DAPT (long-term DAPT) after DES

to determine the optimal duration of DAPT

implantation

in

patients

with

coronary

artery

after DES implantation (5–9). Although inconsistent

disease. It was performed from December 2011 to June

and contradictory results were

obtained, these

2015 at 130 Japanese institutions (Online Appendix).

studies also suggested that bleeding complications

DAPT was aspirin (81 to 162 mg/day) combined with

may be the major drawback of long-term DAPT.

clopidogrel (75 mg/day) or ticlopidine (200 mg/day). During hospitalization for percutaneous coronary

SEE PAGE 1199

intervention (PCI), patients were assigned to 6 or Therefore, although the optimal duration of DAPT

18 months of DAPT at a 1:1 ratio by central randomi-

after DES implantation remains unclear, the data

zation using an interactive web-based system. This

obtained so far suggest that it is important to evaluate

study was designed to approximate an all-comers trial

the net clinical benefit of DAPT by comparing the

with broad inclusion criteria to reflect the real-world

reduction of cardiovascular events with the risk of

clinical setting, and it enrolled patients with acute

bleeding events. Recent advances in DES technology

myocardial infarction (MI). The exclusion criteria

have included the introduction of stents that have a

were in-stent restenosis (bare-metal stent or DES)

biodegradable polymer abluminal coating, and clin-

and index PCI for saphenous vein graft disease or

ical trials have demonstrated a better safety profile

unprotected left main trunk disease. The inclusion and

of

with

exclusion criteria are detailed in the Online Appendix.

first-generation DES (10,11). The NIPPON (Nobori

A maximum of 4 analyses (3 blinded interim analyses

such

second-generation

DES

compared

Cardiology, Komaki City Hospital, Komaki, Japan; nDepartment of Cardiology, Kakogawa Central City Hospital, Kakogawa, Japan; o

Department of Cardiology, St. Luke’s International Hospital, Tokyo, Japan; pDivision of Cardiology, St. Marianna University

School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan; qDivision of Cardiology, Osaka General Medical Center, Osaka, Japan; rDepartment of Cardiovascular Medicine, Omihachiman Community Medical Center, Omihachiman, Japan; sDepartment of Cardiology, Hyogo Brain and Heart Center, Himeji, Japan; tDepartment of Cardiology, Juntendo University Nerima Hospital, Tokyo, Japan; uCardiovascular Center, Toranomon Hospital, Tokyo, Japan; vDivision of Cardiology and Cardiac Catheterization Laboratories, Showa University Northern Yokohama Hospital, Yokohama, Japan; wDepartment of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan; and the xDepartment of Cardiovascular Medicine Center, Fukuoka Sanno Hospital, Fukuoka, Japan. Funded by the Association for Establishment of Evidence in Interventions. Dr. Nakamura has received research grant support and honoraria from Terumo Corporation, Sanofi, and Daiichi-Sankyo. Dr. Iijima has received honoraria from Terumo, Daiichi-Sankyo, Sanofi, and Bayer Yakuhin. Dr. Shinke has received research grant support from Terumo Corporation; and honoraria from Terumo Corporation, Daiichi-Sankyo, and Sanofi. Dr. Ueda has received honoraria for lectures from Daiichi-Sankyo, Novartis, AstraZeneca, MSD, Goodman, Sanofi, Abbott Vascular, Eisai, Toaeiyo, Mochida, Takeda, Boehringer Ingelheim, BristolMyers Squibb, Kowa, Sumitomo Dainippon Pharma, Teijin, Boston Scientific, Astellas, and Amgen Astellas BioPharma; and has received research grants from Abbott Vascular, Pfizer, Sanofi, Bayer, Ono Pharmaceutical, Nihon Kohden, and Novartis. Dr. Morita has received honoraria from Terumo Corporation, Daiichi-Sankyo, and Sanofi. Dr. Ochiai has been an expert witness for Terumo Corporation. Dr. Kawaguchi has received honoraria from Terumo Corporation. Dr. Yokoi has received honoraria from Terumo Corporation and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 3, 2017; accepted April 6, 2017.

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

Short-Term Versus Long-Term DAPT After Nobori Stenting

F I G U R E 1 Flow Diagram Showing the Design of the NIPPON Study

AE ¼ adverse event(s); DAPT ¼ dual antiplatelet therapy; ITT ¼ intention to treat.

and 1 final analysis) were prospectively planned. To

event

control the Type I error, the maximum sample size

enrollment than anticipated, so the executive com-

was calculated to be 4,598 patients (2,299 patients

mittee decided to terminate enrollment in June

per group) by a group-sequential method using the

2015. In addition, the DAPT trial demonstrated the

Lan-DeMets error-spending method (12) with the

advantages of long-term DAPT, especially in patients

O’Brien-Fleming–type boundary, with the interim

with acute coronary syndrome (9). Taken together,

analyses being planned at equally spaced points

the choice of DAPT duration in this study was left up

during data accumulation (25%, 50%, and 75% of

to the attending physician for the patients already

the total data). The first interim analysis was sched-

enrolled.

rates

in

1

treatment

group

and

slower

uled after follow-up of 1,500 patients for 18 months.

The study protocol was approved by the institu-

This analysis showed substantially lower overall

tional review board at each participating center.

1191

1192

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

Short-Term Versus Long-Term DAPT After Nobori Stenting

T A B L E 1 Demographic Profile of the Subjects

T A B L E 2 Lesion and Procedural Characteristics

Long-Term DAPT (n ¼ 1,653)

Short-Term DAPT (n ¼ 1,654)

Age, yrs

67.2  9.9

67.4  9.6

Male

1,312 (79.4)

1,304 (78.8)

Body mass index, kg/m2

24.3  3.5

24.5  3.5

Diabetes mellitus

635 (38.4)

619 (37.4)

Hypertension

1,209 (73.1)

1,177 (71.2)

Hyperlipidemia

1,132 (68.5)

1,130 (68.3)

Current or recent smoker

997 (60.3)

960 (58.0)

Target coronary artery

195 (11.8)

201 (12.2)

Previous PCI

Short-Term DAPT

1,903

1,893

16 (0.8)

7 (0.4)

Left anterior descending

998 (52.4)

981 (51.8)

Left circumflex

374 (19.7)

381 (20.1)

Right coronary artery

515 (27.1)

524 (27.7)

A/B1

321/613

334/603

B2/C

682/405

653/438

Left main

ACC/AHA classification

Medical history Previous MI

Long-Term DAPT

Number of treated vessels

432 (26.1)

413 (25.0)

1

1,346 (81.4)

1,360 (82.2)

Previous CABG

29 (1.8)

22 (1.3)

2

256 (15.5)

226 (13.7)

Previous stroke

41 (2.5)

48 (2.9)

3

51 (3.1)

68 (4.1)

Peripheral artery disease

44 (2.7)

62 (3.7)

Number of Nobori stents per patient

1.5  0.8

1.4  0.8

Previous bleeding peptic ulcer

6 (0.4)

7 (0.4)

Stent diameter

3.1  0.4

3.1  0.4

Minimum stent diameter

Clinical presentation STEMI NSTEMI

196 (11.9)

198 (12.0)

<3 mm

561 (33.9)

563 (34.0)

26 (1.6)

33 (2.0)

$3 mm

1,092 (66.1)

1,091 (66.0)

20.3  5.0

20.1  5.1

Unstable angina

330 (20.0)

296 (17.9)

Stable angina

734 (44.4)

805 (48.7)

Other

275 (16.6)

268 (16.2)

Total stent length, mm Values are n, n (%), or mean  SD.

ACC/AHA ¼ American College of Cardiology/American Heart Association; DAPT ¼ dual antiplatelet therapy.

Medical treatment Aspirin

1,650 (99.8)

1,651 (99.8)

Ticlopidine

44 (2.7)

32 (1.9)

Clopidogrel

1,605 (97.1)

1,619 (97.9)

3 (0.2)

1 (0.1)

STUDY ENDPOINTS. The primary endpoint was net

Statin

1,283 (77.6)

1,290 (78.0)

adverse clinical and cerebrovascular events (NACCE)

ACE-ARB

984 (59.5)

933 (56.4)

(defined as all cause death, Q-wave or non–Q-wave MI,

b-Blocker

600 (36.3)

601 (36.3)

cerebrovascular events, and major bleeding events)

PPI

1,118 (67.6)

1,143 (69.1)

from 6 to 18 months after DES implantation. Major

H2 blocker

107 (6.5)

104 (6.3)

Vitamin K antagonist

29 (1.8)

40 (2.4)

DOAC

44 (2.7)

51 (3.1)

Prasugrel

bleeding was defined by a modification of the criteria used in the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2) study,

Values are mean  SD or n (%).

and

ACE-ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; CABG ¼ coronary artery bypass graft; DAPT ¼ dual antiplatelet therapy; DOAC ¼ direct oral anticoagulant; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; PPI ¼ proton pump inhibitor; STEMI ¼ ST-segment elevation myocardial infarction.

bleeding, retroperitoneal bleeding, clinically evident

included

intracranial

bleeding,

intraocular

bleeding causing a decrease of hemoglobin by >3 g/dl, all bleeding causing a decrease of hemoglobin by >4 g/dl, and bleeding leading to transfusion of packed red blood cells or $2 U of whole blood (13). Major

Written informed consent was obtained from all pa-

bleeding was also evaluated by the Bleeding Academic

tients. This study was conducted in accordance with

Research Consortium (BARC) criteria for type 3 and 5

the Declaration of Helsinki and was registered at

bleeding (14). The main secondary endpoints were: 1)

ClinicalTrials.gov (Nobori Dual Antiplatelet Therapy

NACCE during the entire follow-up period (0 to 18

as Appropriate Duration [NIPPON]; NCT01514227).

months); 2) the incidence of definite or probable stent

STUDY

PROCEDURES

terventions

for

AND

coronary

FOLLOW-UP. All

revascularization

inwere

performed in the real-world clinical setting in accordance with the current Japanese guidelines, and were selected at the discretion of the interventional cardiologist. Clinical follow-up was scheduled at 1, 3, 6, 12, 18, and 36 months after DES implantation,

thrombosis according to the Academic Research Consortium definition (15) from 6 to 18 months after implantation; 3) the incidence of death, MI, and cerebrovascular events from 6 to 18 months after DES implantation; and 4) the incidence of major bleeding events at 18 months. More detailed definitions of the endpoints are provided in the Online Appendix.

but angiographic follow-up was not mandatory.

STUDY

Discontinuation of thienopyridine therapy for at least

data safety monitoring board, and clinical event

ORGANIZATION. The

2 weeks was defined as withdrawal.

committee are listed in the Online Appendix.

steering committee,

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

STATISTICAL ANALYSIS. This study was designed

to demonstrate noninferiority of short-term DAPT

1193

Short-Term Versus Long-Term DAPT After Nobori Stenting

F I G U R E 2 Adherence to DAPT in Both Groups

versus long-term DAPT with a power of 90% and a significance of 2.5% for the 1-sided, chi-square test. The incidence of the primary endpoint (NACCE from 6 months to 18 months) was assumed to be 4.5% in both the long-term and short-term DAPT groups, with the noninferiority margin being set at 2.0%. Analyses were primarily performed on an intention-to-treat (ITT) basis. For assessment of noninferiority, the 95% confidence interval (CI) of the difference in the event rate (determined by subtracting the rate in the short-term DAPT group from that in the long-term DAPT group) was calculated by using the NewcombeWilson method, and noninferiority was accepted if the lower limit of the 95% CI was more than
2.0. An “as-treated” analysis was also conducted to evaluate the robustness of the results obtained by ITT analysis. Event rates with 95% CIs were calculated. KaplanMeier survival analysis was also conducted, and

Red line ¼ 6-month DAPT group; blue line ¼ 18-month DAPT group. DAPT ¼ dual antiplatelet therapy.

survival event curves were compared by using the log-rank test. Categorical variables were described as numbers and proportions. Analysis of categorical variables was performed using the chi-square test or Fisher exact test, whereas continuous variables were analyzed with the Student t test or Wilcoxon rank test. The Cox proportional hazard (PH) model was used to calculate the hazard ratio (HR) and 95% CI. The treatment-by-subgroup interaction was assessed for all subgroups, either by calculating HRs between subgroups or by using the interaction terms in the Cox PH model. All p values were 2-sided, and p < 0.05 was considered to indicate statistical significance. All statistical analyses were performed with SAS version 9.3 for Windows (SAS Institute, Cary, North Carolina).

acute coronary syndrome in 33.5% of the long-term DAPT group and 31.9% of the short-term DAPT group. Procedural and angiographic characteristics of the 2 groups are displayed in Table 2. There were no significant differences of procedural characteristics, including the number of stents, stent length, and stent size. The left anterior descending coronary artery was the target vessel for revascularization in 52.4% and 51.8% of patients, respectively. Adherence to DAPT in each group is summarized in Figure 2. The demographic

PATIENT POPULATION. Figure 1 shows a flowchart of

the trial. Of the 3,773 patients enrolled, 3,307 patients were followed for at least 6 months and were analyzed for the primary endpoint. Seventeen patients in the long-term DAPT group and 13 patients in

angiographic

findings

of

the

enrolled in the “as treated” analysis are listed in the Online Tables S1 to S4. PRIMARY

RESULTS

and

patients who received allocated treatment and those

AND

SECONDARY

ENDPOINTS. The

median follow-up period was 435 days (quartile 1 to

T A B L E 3 Clinical Outcomes and Bleeding Complications

Outcome 6–18 Months

NACCE

Long-Term DAPT (n ¼ 1,653)

Short-Term DAPT (n ¼ 1,654)

%Difference* (95% CI)†

24 (1.5)

34 (2.1)


0.6 (
1.5 to 0.3)

0.24

16 (1.0)


0.5 (
1.2 to 0.0)

0.09

p Value‡

All-cause death

7 (0.4)

the short-term DAPT group were excluded from the

Cardiovascular

4 (0.2)

8 (0.5)


0.2 (
0.7 to 0.2)

0.39

“as treated” analysis because they did not receive

Noncardiovascular

3 (0.2)

8 (0.5)


0.3 (
0.8 to 0.1)

0.23 0.37

DAPT. The profile of the subjects who were followed

Nonfatal MI

1 (0.1)

4 (0.2)


0.2 (
0.6 to 0.1)

up for 6 to 18 months is shown in Table 1. There were

Nonfatal stroke

6 (0.3)

7 (0.4)


0.1 (
0.6 to 0.4)

1.00

no significant differences of baseline characteristics

Major bleeding

12 (0.7)

11 (0.7)

0.1 (
0.6 to 0.7)

0.84

between the short-term and long-term DAPT groups.

Stent thrombosis

1 (0.1)

2 (0.1)


0.1 (
0.4 to 0.2)

1.00

Mean age was 67.2  9.9 years in the long-term DAPT group and 67.4  9.6 years in the short-term DAPT group. The prevalence of diabetes was approximately 40% in both groups. Index PCI was performed for

Values are n (%) except as noted. *%Difference ¼ long-term DAPT
short-term DAPT. †Newcomb score-type confidence interval (CI). ‡Fisher exact test. CV ¼ cardiovascular; DAPT ¼ dual antiplatelet therapy; MI ¼ myocardial infarction; NACCE ¼ composite event of all-cause death, nonfatal myocardial infarction, nonfatal stroke, or major bleeding.

1194

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

Short-Term Versus Long-Term DAPT After Nobori Stenting

F I G U R E 3 Kaplan-Meier Estimates of the Probability of NACCE Occurring Between

6 and 18 Months

individual components of NACCE from 0 to 18 months are depicted in Online Table S5 and Online Figures S2 and S3. BLEEDING COMPLICATIONS. From 6 to 18 months

after stenting, major bleeding events occurred in 12 patients (0.7%) from the long-term DAPT group and 11 patients (0.7%) from the short-term DAPT group. Table 4 shows the bleeding events categorized according to the modified REPLACE-2 criteria, BARC criteria, and cause. INTERACTIONS

When

potential

WITH

THE

PRIMARY

interactions

with

ENDPOINT.

NACCE

were

analyzed in pre-specified subgroups (Figure 5), consistent outcomes were obtained among various clinical subsets. However, a marginal interaction was observed in relation to the number of stents, because multiple stenting was associated with a higher rate of NACCE in the short-term DAPT group. All of these results were confirmed by “as treated” analysis (Online Figure S4). Short-term DAPT was not inferior to long-term DAPT in terms of NACCE. However, the curves diverged and there was a higher event rate with short-term DAPT (2.4%) than long-term DAPT (1.7%). Red line ¼ 6-month DAPT; blue line ¼ 18-month DAPT. CI ¼ confidence interval; DAPT ¼ dual antiplatelet therapy; HR ¼ hazard ratio; M ¼ month; NACCE ¼ net adverse clinical and cerebrovascular event(s).

DISCUSSION The NIPPON trial was a multicenter RCT that was performed to evaluate the optimal duration of DAPT after implantation of DES with a biodegradable abluminal coating. On the basis of current knowledge,

quartile 3: 365 to 540 days) in the long-term DAPT

the combination of short-term DAPT and a second-

group and 430 days (quartile 1 to quartile 3: 361 to 540

generation DES with a biodegradable abluminal

days) in the short-term DAPT group. The primary

coating should simultaneously minimize the inci-

endpoint was reached by 24 patients in the long-term

dence of thrombotic events and bleeding complica-

DAPT group (1.5%) and 34 patients in the short-term

tions. Therefore, we hypothesized that a short

DAPT group (2.1%) (Table 3), with a 0.6% difference

duration of DAPT (6 months) might be acceptable

in the primary endpoint rate between the 2 groups

with this new type of stent. Although the present

(95% CI:
1.5 to 0.3). Because the lower limit of the

findings seem to support the strategy of short-term

95% CI was inside the specified margin of
2%, non-

DAPT after deployment of a newer DES, interpreta-

inferiority of short-term DAPT was confirmed. This

tion of the data in relation to daily practice may be

finding was also confirmed in as treated analysis

difficult, and we should be cautious about drawing

(Online Table S5). Kaplan-Meier survival curves of

conclusions. First, the incidence of the primary

both groups for the primary endpoint are depicted in

endpoint was lower than expected in both groups.

Figure 3. The curves of the 2 groups diverged during

Therefore, the statistical power of our study may not

the follow-up period, and the estimated probability of

have been adequate to fully assess the risk of the

events was numerically higher in the short-term

primary endpoint, and this point deserves emphasis.

DAPT group (HR: 1.44, 95% CI: 0.86 to 2.43). Occur-

It may be reasonable to consider that the enrollment

rence rates for the individual components of the pri-

of relatively low-risk patients resulted in the present

mary endpoint are displayed in Table 3 and Figure 4.

outcome. In fact, the total stent length was about

The Kaplan-Meier mortality curve showed higher

20 mm, and 66% of the stents were >3 mm in size. In

mortality in the short-term DAPT group (HR: 2.25,

this study, the duration of long-term DAPT was set at

95% CI: 0.93 to 5.43; p ¼ 0.05). Definite or probable

18 months. Other recent RCTs have investigated

stent thrombosis occurred in 0.1% of each group

different durations of DAPT after deployment of

from 6 to 18 months. Identical outcomes were

DES, ranging from 3 months up to 30 months.

revealed by “as-treated” analysis (Online Table S5,

Therefore, it is difficult to compare these studies

Online Figure S1). The incidence of NACCE and the

directly in order to elucidate the optimal duration of

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

1195

Short-Term Versus Long-Term DAPT After Nobori Stenting

F I G U R E 4 Kaplan-Meier Estimates of the Probability of Each Component of NACCE From 6 to 18 Months

Red line ¼ 6-month DAPT; blue line ¼ 18-month DAPT. MI ¼ myocardial infarction; other abbreviations as in Figure 3.

DAPT after DES implantation. Moreover, the reported

prolonged

outcomes have been inconsistent. We hypothesized

make it difficult to assess the clinical advantages of

DAPT

(adherence

to

protocol)

could

that the findings of the present study were likely to be

different DAPT durations after DES implantation. This

consistent with the results of previous studies

type of error is also likely to be common in these

demonstrating

studies. For example, 33.8% of patients assigned to the

the

noninferiority

of

short-term

DAPT (5–7). A comparison with these previous RCTs revealed several important similarities among them, including lower event rates than anticipated and

T A B L E 4 Bleeding Complications

slow enrollment resulting in early termination. Although there were some differences with regard

Bleeding Complications 6–18 Months

to the duration of DAPT, the cumulative event rate

REPLACE-2

was similar in our study and in the recent ISAR-

BARC class

Long-Term DAPT (n ¼ 1,653)

Short-Term DAPT (n ¼ 1,654)

Difference vs. Long-Term DAPT, % (95% CI)

p Value

12 (0.7)

11 (0.7)

0.1 (
0.6 to 0.7)

0.83

0.83

SAFE (Intracoronary Stenting and Antithrombotic

3a

3 (0.2)

4 (0.2)

Regimen: Safety and Efficacy of 6 Months Dual Anti-

3b

5 (0.3)

4 (0.2)

platelet Therapy After Drug-Eluting Stenting) (5) and

3c

2 (0.1)

3 (0.2)

5

2 (0.1)

0

12 (0.7)

11 (0.7)

0.1 (
0.6 to 0.7)

Gastrointestinal bleeding

8 (0.5)

9 (0.5)

0.0 (
0.5 to 0.5)

1.00

Intracranial bleeding

4 (0.2)

3 (0.2)

0.1 (
0.3 to 0.5)

0.73

ITALICplus (Is There a Life for DES After Discontinuation of Clopidogrel) (6) studies. These findings, together with slow enrollment, might reflect selection

BARC 3 þ 5

bias in all of the studies. Thus, selection bias favoring lower-risk patients may be a common feature of trials

Values are n (%) except as noted.

assessing DAPT (5–8). Furthermore, early termination

BARC ¼ Bleeding Academic Research Council; REPLACE ¼ randomized evaluation in PCI linking angiomax to reduced clinical events; PCI ¼ percutaneous coronary intervention.

of DAPT in some patients and switching of others to

1196

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017

Short-Term Versus Long-Term DAPT After Nobori Stenting

JUNE 26, 2017:1189–98

F I G U R E 5 Occurrence of NACCE in Specified Subgroups

ACS ¼ acute coronary syndrome; DM ¼ diabetes mellitus; PPI ¼ proton pump inhibitor; other abbreviations as in Figure 3.

6-month group in the SECURITY (Second Generation

that this outcome simply reflected different risks of

Drug-Eluting Stent Implantation Followed by Six-

cardiovascular events in the 2 groups. In fact, the

Versus Twelve-Month Dual Antiplatelet Therapy)

noncardiovascular death rate after 6 months was also

study were still receiving treatment at 12 months (7),

higher in the short-term DAPT group.

whereas 353 patients (19%) discontinued treatment

The outcomes of our sensitivity analyses were

prematurely or received it for longer than specified in

consistent with the main findings, although the

the ITALICplus study (6).

marginal interaction between the number of stents

This study was based on the hypothesis that using a

and NACCE may be meaningful. An influence of

DES with biodegradable abluminal polymer coating

the number of stents deployed is consistent with a

may reduce the risk of future events including

recent meta-analysis, which showed that procedural

stent thrombosis. The safety of DES coated with

complexity is an important factor when considering

biodegradable polymers has been confirmed by

prolonged DAPT (19). Taken together, it seems

previous RCTs (16,17). However, absorption of the

reasonable to conclude that our findings strengthen

polymer coating of the Nobori stent takes longer than

the recent emphasis on the importance of personal-

6 months (16), suggesting that mismatch between the

ized DAPT to avoid bleeding and thrombotic events.

polymer degradation time and the duration of DAPT

Major bleeding complications were not different

may have resulted in adverse outcomes in the short-

in the 2 groups. This finding is also consistent with

term DAPT group. An on-going trial using a DES with

the outcomes of previous RCTs demonstrating non-

an abluminal polymer coating that shows more rapid

inferiority of short DAPT (5,6). However, it is not

degradation than that of the Nobori stent may enhance

in agreement with the results of the DAPT trial or

understanding of the importance of the polymer

with the findings of meta-analysis (9,20). There may

degradation time (18). Another possible explanation is

be several reasons why long-term DAPT was not

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

Short-Term Versus Long-Term DAPT After Nobori Stenting

associated with a higher rate of bleeding. First, our

provided with clopidogrel in the present study, so use

study may not have been adequately powered to

of more potent antiplatelet agents may have led to

calculate the risk of individual cardiovascular events,

different outcomes. Additionally, generalization of

such as major bleeding. Second, initiation of DAPT is

our results to high-risk patients may require caution.

an important risk factor for bleeding events (21), so

Finally, the follow-up period may not have been

performing analysis after 6 months provides data on

long enough to determine the optimum duration of

outcomes in patients who have tolerated DAPT.

DAPT after DES implantation, because the DAPT trial

Actually, more than 50% of the major bleeding events

has demonstrated the benefit of continuing DAPT for

occurred within 6 months of starting DAPT in the

30 months (9). Thus, a further long-term study may

present study, with the subsequent bleeding event

be warranted in the future.

rate being <1% in both groups. Third, the lower-thananticipated event rate suggests that our subjects also

CONCLUSIONS

had a lower risk of bleeding, because these risks frequently coexist and are difficult to discriminate

In this study, 6 months of DAPT showed non-

from each other (22). Finally, a low frequency of

inferiority to 18 months of DAPT in terms of NACCE

gastrointestinal bleeding may have been a factor in

after implantation of DES with a biodegradable

the present cohort because proton pump inhibitors or

abluminal coating. However, the results need to be

histamine 2 blockers were prescribed for more than

interpreted with caution due to premature termina-

70% of patients in both groups, whereas the pre-

tion of enrollment and the open-label design with a

scription rate of proton pump inhibitors was only

wide noninferiority margin.

around 30% in the ISAR-SAFE study (5). A large-scale registry study has shown that approximately 60%

ADDRESS

of bleeding originates from the gastrointestinal

Nakamura, Division of Cardiovascular Medicine, Toho

tract (23), and the protective effect of proton pump

University Ohashi Medical Center, 2-17-6 Ohashi,

inhibitors against bleeding due to nonsteroidal anti-

Meguro-ku, Tokyo 153-8515, Japan. E-mail: masato@

inflammatory drugs has been thoroughly demon-

oha.toho-u.ac.jp.

FOR

CORRESPONDENCE:

Dr.

Masato

strated (24,25). Physicians should be cautious about the risk of gastrointestinal bleeding in both patients receiving DAPT and those on antiplatelet mono-

PERSPECTIVES

therapy. On the other hand, it should be kept in mind that BARC 5 bleeding was only observed in the

WHAT IS KNOWN? The optimal duration of DAPT after DES

18-month DAPT group.

implantation remains unclear, so evaluation of the net clinical

STUDY

LIMITATIONS. In

addition to the points

benefit of DAPT (balance between bleeding complications and

mentioned in the preceding text, several important

reduction of cardiovascular events) is crucial. Recent advances in

limitations need to be taken into consideration. First,

DES technology have improved the safety profile compared with

this was not a double-blind trial. As a result, early

first-generation DES.

termination of DAPT and switching to prolonged DAPT occurred in a substantial number of subjects. The low thrombotic event rate in the present study could be partly explained by the meticulous stent deployment procedure that was used. However, the observed events rate was lower than anticipated, making this study underpowered relative to the initial calculations. Therefore, interpretation of our findings should be done with caution, especially with regard to the interactions between outcomes. Furthermore,

antiplatelet

therapy

was

WHAT IS NEW? After biodegradable polymer DES deployment, short-term DAPT is not inferior to long-term DAPT in relatively low-risk patients. Our findings support the recent emphasis on the importance of personalized DAPT to avoid bleeding and thrombotic events. WHAT IS NEXT? Further studies are needed to establish ideal risk stratification schemes for patients undergoing deployment of contemporary DES.

mainly

REFERENCES 1. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis

2. Mauri L, Hsieh WH, Massaro JM, Ho KK, D’Agostino R, Cutlip DE. Stent thrombosis in ran-

3. Kimura T, Morimoto T, Nakagawa Y, et al. Antiplatelet therapy and long-term clinical outcome after sirolimus-

after successful implantation of drug-eluting stents. JAMA 2005;293:2126–30.

domized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–9.

eluting stent implantation: 5-year outcome of the jCypher registry. Cardiovasc Interv Ther 2012;27:181–8.

1197

1198

Nakamura et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 12, 2017 JUNE 26, 2017:1189–98

Short-Term Versus Long-Term DAPT After Nobori Stenting

4. Valgimigli M, Campo G, Monti M, et al., Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term dura-

stents in patients with acute ST-segment elevation myocardial infarction: a pooled analysis of the EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial INfArcTION) and

tion of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–26.

COMFORTABLE-AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction) trials. J Am Coll Cardiol Intv 2014;7: 55–63.

5. Schulz-Schüpke S, Byrne RA, Ten Berg JM, et al., Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J 2015;36: 1252–63. 6. Gilard M, Barragan P, Noryani AA, et al. Sixmonth versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol 2015;65: 777–86. 7. Colombo A, Chieffo A, Frasheri A, et al. Secondgeneration drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014;64:2086–97. 8. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125:505–13. 9. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drugeluting stents. N Engl J Med 2014;371:2155–66. 10. Stefanini GG, Byrne RA, Serruys PW, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012;33:1214–22. 11. Sabaté M, Räber L, Heg D, et al. Comparison of newer-generation drug-eluting with bare-metal

12. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35: 549–56. 13. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–63. 14. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123: 2736–47. 15. Cutlip DE, Windecker S, Mehran R, et al., Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: 2344–51. 16. Natsuaki M, Kozuma K, Morimoto T, et al. Final 3-year outcome of a randomized trial comparing second-generation drug-eluting stents using either biodegradable polymer or durable polymer: NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial. Circ Cardiovasc Interv 2015;8:e002817. 17. Han Y, Xu B, Xu K, et al. Six versus 12 months of dual antiplatelet therapy after implantation of biodegradable polymer sirolimuseluting stent: randomized substudy of the I-LOVE-IT 2 trial. Circ Cardiovasc Interv 2016;9:

intervention with early discontinuation of dualantiplatelet therapy. J Invasive Cardiol 2017;29: 36–41. 19. Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after Complex PCI. J Am Coll Cardiol 2016;68: 1851–64. 20. Spencer FA, Prasad M, Vandvik PO, Chetan D, Zhou Q, Guyatt G. Longer- versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis. Ann Intern Med 2015;163:118–26. 21. Ko DT, Yun L, Wijeysundera HC, et al. Incidence, predictors, and prognostic implications of hospitalization for late bleeding after percutaneous coronary intervention for patients older than 65 years. Circ Cardiovasc Interv 2010;3:140–7. 22. Matteau A, Yeh RW, Camenzind E, et al. Balancing long-term risks of ischemic and bleeding complications after percutaneous coronary intervention with drug-eluting stents. Am J Cardiol 2015;116:686–93. 23. Généreux P, Giustino G, Witzenbichler B, et al. Incidence, predictors, and impact of postdischarge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015;66:1036–45. 24. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346:2033–8. 25. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909–17.

KEY WORDS biodegradable polymer, drug-eluting stent(s), dual antiplatelet therapy, net adverse clinical and cerebrovascular event(s), stent thrombosis

e003145. 18. Noad RL, Hanratty CG, Walsh SJ. Initial experience of bioabsorbable polymer everolimuseluting synergy stents in high-risk patients undergoing complex percutaneous coronary

A PPE NDI X For an expanded Methods section, list of investigators, and supplemental tables and figures, please see the online version of this article.