6 months versus 18 months dual antiplatelet treatment

for patients underwent bioabsorbable polymer and

abluminal coated DES deployment: NIPPON randomized study

Masato Nakamura, Raisuke Iijima, Junya Ako, Toshiro Shinke,

Hisayuki Okada,Yoshiaki Ito, Kenji Ando, Hitoshi Anzai, Hiroyuki Tanaka, Yasunori Ueda, Shin Takiuchi, Yasunori Nishida, Hiroshi Ohira,

Katsuhiro Kawaguchi, Makoto Kadotani, Hiroyuki Niinuma, Kazuto Omiya, Takashi Morita, Kan Zen, Yoshinori Yasaka, Kenji Inoue, SugaoIshiwata, Masahiko Ochiai, Toshimitsu Hamasaki, and Hiroyoshi Yokoi,

on behalf of the NIPPON investigators

COI Disclosure

Name of First Author : Masato Nakamura

• Grants from Terumo corp. Daiichi Sankyo

and Sanofi KK outside the submitted work

• Honoraria from Terumo corp. Daiichi

Sankyo KK, Astra-Zeneka KK, and Sanofi

KK.

Background 1

• Previous trials yielded inconsistent and

even contradictory results about dual

antiplatelet treatment (DAPT) duration

following drug eluting stent (DES)

deployment.

• In general, prolonged DAPT associated

with higher bleeding risk concomitant with

lower event risk

Background 2

• Utilized DES in the previous trials was

not homogenous

• Clinical trials have demonstrated a better

safety profile of 2nd generation DES

compared with 1st generation DES

• Recent advances in DES technology

introduced stents that have an abluminal

coating with bioabsorbable polymers

Objectives

• NIPPON trial is a multi-center randomized

study to test the non-inferiority of 6 months

DAPT compared with 18 months DAPT

following NOBORI stent

• NOBORI is a DES with bioabsorbable

polymer and abluminal coating

• Clinical trial:NCT.01514227

Inclusion criteria

1. Subject was > 20 years and <80 years of age

2. Subjects had optimal indication for undergoing

percutaneous intervention

3. Subjects without known contraindication to dual

antiplatelet therapy

4. Subject had consented to participate and had

authorized the collection and release of his

medical information by signing the “Patient

Informed Consent Form”.

Main Exclusion criteria1.Subject was cardiogenic shock at the time of PCI

2.Cardiac ejection fraction was <30%

3.Subject had a history of stent thrombosis

4.Subjects with hypersensitivity or allergies to one of the drugs or

components indicated in the “Instructions for Use” for the device

implanted.

5.Life expectancy was < 1year

6.Subject’s status was active bleeding condition

7.Incompetency to undergo all clinical FUs

8.Planned surgery necessitating discontinuation of antiplatelet

therapy (>14 days) within the 18 months following enrollment.

9.Index procedure stent placement for saphenous vein graft, in-

stent restenosis of DES, or unprotected LMT disease

10.Subject had a history of intracranial bleeding or ischemic stroke

within 6 months before enrollment.

Primary endpoint : The incidence of net adverse clinical and

cerebrovascular events (NACCE*) between 6 to 18 months after DES

implantation for safety.

Secondary endpoints :

1) The incidence of definite or probable stent thrombosis at 18 months

2) The incidence of death, MI and cerebrovascular events at 18 months

3) The incidence of major bleeding events at 18 months after DES

implantation.

*All cause death, a Q-wave or non-Q wave MI, cerebrovascular events, or major

bleeding events that are defined in modified REPLACE-2 studies or Bleeding

Academic Research Consortium (BARC) criteria.

Endpoints

1. The present study was designed to analyze non-inferiority

having a statistical power of 90% and a one-sided type I error

of 2.5%.

2. The presumed incidence of NACCE from 6 months to 18

months was 4.5 % in prolonged DAPT group with a non-

inferiority margin of 2.0% for the short DAPT group.

3. Maximum four analyses (three interim and one final analyses)

were prospectively planned for earlier stopping of efficacy and

a maximum sample size of 4,598 patients was calculated by a

group-sequential method to control the Type I error using Lan–

DeMets error-spending method with the O’Brien–Fleming-type

boundary.

Statistical Methods

Statistical Methods 2

• Protocol scheduled interim analysis after 18

months follow up of 1500 patients. This blinded

analysis showed lower overall event rates than

expected ones, along with slower enrolment than

anticipated, the executive committee decided to

terminate the enrollment in June 2015.

• This statistical analysis was performed according

to the ITT principle, with the inclusion of

consecutive patients who were eligible to conduct

18-month follow-up at the time of enrollment

termination.

Flow Chart of NIPPON trial Randomized (N=2772)

Allocation

Analysis

≥18 months after enrollment

(N=2772)

Enrolled and

Randomized (N=3775)

Excluded due to

follow-up <18 months (n=1003 )

Follow-up

18 months follow-up (n=1306)

Death (n=13)

Declined to participate (n=2)

Lost to FU (n=70)

18 months follow-up (n=1286)

Death (n=16)

Declined to participate (n=1)

Lost to FU (n=78)

On Treatment (OT)

n=1383

Intention-to-Treat (ITT)

N=1391

On Treatment (OT)

n=1378

Intention-to-treat (ITT)

n=1381

Allocated to 18 months DAPT

(n=1391)

Received allocated intervention

(n=1391)

Excluded (n=0)

Allocated to 6 months DAPT

(n=1381)

Received allocated intervention

(n=1381)

Excluded (n=0)

Variable

N

Age (yrs)

Male

Body Mass Index (kg/m2)

Diabetes mellitus

Hypertension

Hyperlipidemia

Current or recent smoker

Medical History

Prior MI

Prior PCI

Prior CABG

Prior stroke

Peripheral artery disease

Previous bleeding peptic ulcer

Clinical presentation

STEMI

NSTEMI

Unstable angina

Stable angina

Other

18 months DAPT(%)

1391

66.9±9.8

1113 (80.0)

24.3±3.5

550 (39.5)

1023 (73.5)

948 (68.2)

844 (60.7)

176 (12.7)

398 (28.6)

24 (1.7)

40 (3.0)

35 (2.5)

16 (1.2)

142 (10.4)

18 (1.3)

277 (19.1)

633 (45.5)

224 (16.1)

6 months DAPT(%)

1381

67.1±9.6

1095 (79.3)

24.4±3.5

529 (38.3)

993 (71.9)

934 (67.6)

813 (58.9)

181 (13.1)

364 (26.4)

21 (1.5)

42 (3.0)

57 (4.1)

9 (0.7)

140 (10.1)

27 (2.0)

243 (17.6)

656 (46.8)

233 (16.9)

Target lesion coronary artery

Left main

Left anterior descending

Left circumflex

Right coronary artery

ACC/AHA classification

A/B1

B2/C

Number of treated vessel

1-vessel

2-vessel

3-vessel

Number of NOBORI stent per patient

Stent diameter (mean ± SD)

Minimum stent diameter

<3mm

≥3mm

Total stent length (mean ± SD)

18 months DAPT

15 (1.1)

846 (60.8)

317 (22.8)

426 (30.6)

283/523

565/335

1189 (85.5)

179 (12.9)

23 (1.7)

1.5±0.8

3.0±0.4

491 (35.3)

897 (64.5)

20.3±5.0

6 months DAPT

4 (0.3)

822 (59.5)

313 (22.7)

421 (30.5)

294/489

540/348

1215 (88.0)

143 (10.4)

23 (1.7)

1.4±0.8

3.0±0.4

498 (36.0)

882 (63.9)

20.1±5.1

18 months

DAPT

n=1371

1.45 %

6 months

DAPT

n=1355

1.92 %

Difference -0.46

Lower limit of 95% CI -1.48

Newcombe

score method

Favor 6 months

Favor 18 months DAPT

Pre-specified non inferiority

margin=-2.0

Primary Non-Inferiority Endpoint Met

1.00-1-2-3-4

Primary endpoint (NACCE)

0 6 9 12 15 18

Months since Enrollment

01

.02

.03

.04

.05

.06

.0

Cu

mu

lative

In

cid

en

ce

(%

)

HR: 1.320(95%CI: 0.737, 2.365)

Long-term DAPT

Short-term DAPT

1377 1355 1351 1319 1290

1357 1340 1332 1289 1276

At risk

Long-term DAPT

Short-term DAPT

0 3 6 9 12 15 18

Months since Enrollment

01

.02

.03

.04

.05

.06

.0

Cu

mu

lative

In

cid

en

ce

(%

)

HR: 1.114 (95%CI: 0.729, 1.700)

Long-term DAPT

Short-term DAPT

1391 1355 1337 1308 1284 1231 1081

1381 1351 1334 1285 1251 1184 1143

At risk

Long-term DAPT

Short-term DAPT

K-M curve of NACCE

during 0-18 months

K-M curve of NACCE

during 6-18 months

1.45

0.51

0.070.29

0.07

0.73

1.92

0.74

0.220.3

0.07

0.96

NACCE DEATH MI STROKE STENT THROMBOSIS

BLEEDING

18 months DAPT

6 months DAPT

P=0.37

P=0.37

P=0.48

P=1.00P=1.00

P=0.54

Primary and secondary endpoints

(6-18 months)

Fisher’ｓ exact test

Bleeding complication 6-18M

0.73

0.15

0.22 0.22

0.15

0.36

0.15

0.96

0.37 0.37

0.15

0.59

0.15

REPLACEⅡ BARC 3A BARC 3B BARC 3C BARC 5 GI BLEEDING INTRACRANIAL

18 months DAPT 6 months DAPT

P=0.54

P=0.42

P=1.00

P=0.67

Fisher’ｓ exact test

Overall

Age

Age<65

Age>65

Sex

Female

Male

ACS

No ACS

ACS

DM

No DM

DM

Hypertension

No

Yes

Statin

No statin

Statin

PPI

No PPI

PPI

Number of stent

<1

>1

Long -term

DAPT

20/1377

8/530

12/847

3/274

17/1103

13/942

7/435

12/834

8/543

3/361

17/1013

8/308

12/1068

4/470

16/905

15/942

5/434

Short -term

DAPT

26/1357

4/546

22/811

4 / 278

22/1079

15/955

11/402

13/841

13/516

5/380

21/977

10/294

16/1062

11/453

15/903

15/972

11/385

(%)

(1.4 5)

(1.51)

(1.42)

(1.09)

(1.54)

(1.38)

(1.61)

(1.44)

(1.47)

(0.83)

(1.68)

(2.60)

(1.12)

(0.85)

(1.77)

(1.59)

(1.15)

(%)

(1.92)

(0.73)

(2.71)

(1.44)

(2.04)

(1.57)

(2.74)

(1.55)

(2.52)

(1.32)

(2.15)

(3.40)

(1.51)

(2.43)

(1.66)

(1.54)

(2.86)

P -value

(logrank)

0.32

0.24

0.06

0.76

0.34

0.71

0.25

0.82

0.22

0.50

0.43

0.53

0.42

0.06

0.88

0.95

0.07

p-value

Interaction

0.07

0.90

0.53

0.47

0.74

0.98

0.12

0.16

6M better 18M better

Occurrence of NACCE in specified subgroups ITT analysis

• This was not a double-blind trial, as a result, adherence of

drug was problematic in the present study.

• This trial was not adequately powered due to lower event

rate than anticipated and wide non-inferiority margin.

• Premature termination of the present study concomitant

with the enrollment of relatively low risk subject suggest

that the generalization of our results to high-risk patients

requires caution.

• Antiplatelet therapy was mainly limited to clopidogrel in our

study, so use of more potent antiplatelet agents may have

led to different conclusions.

• The follow-up period may not have been long enough to

draw conclusions about the optimum of duration of DAPT

for patients with DES, because the DAPT trial

demonstrated the benefit of prolonged DAPT for 30 months

Study limitation

Adherence of DAPT:

Early termination, and cross over to DAPT was frequent

18 months

DAPT

n=1371

1.45 %

6 months

DAPT

n=1355

1.92 %

Difference -0.46

Lower limit of 95% CI -1.48

Met the non-

inferiority

Favor 6 months

Favor 18 months DAPT

Pre-specified non inferiority

margin=-2.0

1.00-1-2-3-4

Primary endpoint (NACCE)

The presumed incidence of NACCE from 6 months to 18 months was

4.5 % in prolonged DAPT group with a non-inferiority margin of 2.0%.

• This was not a double-blind trial, as a result, adherence of

drug was problematic in the present study.

• This trial was not adequately powered due to lower event

rate than anticipated and wide non-inferiority margin.

• Premature termination of the present study concomitant

with the enrollment of relatively low risk subject suggest

that the generalization of our results to high-risk patients

requires caution.

• Antiplatelet therapy was mainly limited to clopidogrel in our

study, so use of more potent antiplatelet agents may have

led to different conclusions.

• The follow-up period may not have been long enough to

draw conclusions about the optimum of duration of DAPT

for patients with DES, because the DAPT trial

demonstrated the benefit of prolonged DAPT for 30 months

Study limitation

• This was not a double-blind trial, as a result, adherence of drug was

problematic in the present study.

• This trial was not adequately powered due to lower event rate than

anticipated and wide non-inferiority margin.

• Premature termination of the present study concomitant with the

enrollment of relatively low risk subject suggest that the generalization

of our results to high-risk patients requires caution.

• Antiplatelet therapy was mainly limited to clopidogrel in our study, so

use of more potent antiplatelet agents may have led to different

conclusions.

• The follow-up period may not have been long enough to draw

conclusions about the optimum of duration of DAPT for patients with

DES, because the DAPT trial demonstrated the benefit of prolonged

DAPT for 30 months

Study limitation

6 months of DAPT was statistically non-inferior to

18 months of DAPT in terms of net adverse clinical

and cerebrovascular events, including all cause

death, Q-wave or non-Q wave MI, cerebrovascular

events, and major bleeding.

However, the results need to be interpreted with

caution given premature termination of enrollment,

an open-label design with frequent crossover and a

wide non-inferiority margin.

Conclusion

Participated center

Hisayuki Okada Seirei Hamamatsu General Hospital

Yoshiaki Ito Saiseikai Yokohama City Eastern Hospital

Hidehiko Hara Toho University Ohashi Medical Center

Kenji Ando Kokura Memorial Hospital

Hitoshi Anzai Ota Memorial Hospital

Hiroyuki Tanaka Tokyo Metropolitan Tama Medical Center

Yasunori UedaNational Hospital Organization Osaka National Hospital

Shin Takiuchi Higashi Takarazuka Satoh Hospital

Yasunori Nishida Takai Hospital

Hiroshi Ohira Edogawa Hospital

Katsuhiro Kawaguchi Komaki City Hospital

Makoto Kadotani, Kakogawa East City Hospital

Hiroyuki Niinuma St. Luke's International Hospital

Kazuto OmiyaSt. Marianna University School of Medicine Yokohama City Seibu Hospital

Takashi Morita Osaka General Medical Center

Kan Zen Omihachiman Community Medical Center

Yoshinori Yaita Hyogo Brain and Heart Center

Kenji Inoue Juntendo University Nerima Hospital

Sugao Ishiwata Toranomon Hospital

Masahiko Ochiai,Showa University Northern Yokohama Hospital

Itaru Takamisawa Sakakibara Heart Institute

Junji Yajima The Cardiovascular Institute

Takayuki Ishihara Kansai Rosai Hospital

Shigeru Nakamura Kyoto Katsura Hospital

Kenshi Fujii Sakurabashi Watanabe Hospital

Kazuhiro Ashida Yokohama Shintoshi Neurosurgical Hospital

Hiroshi Ota Itabashi Central General Hospital

Masaaki Okutsu Nozaki Tokushukai Hospital

Masao Oshima Iseikai Hospital

Ken KongojiSt. Marianna University School of Medicine University Hospital

Yasushi Jinno Handa City Hospital

Ryu Shutta Osaka Rosai Hospital

Nobuo Shiode Tsuchiya General Hospital

Tetsuo Oumi National Diaster Medical Center

Tatsuki Doijiri Yamato Seiwa Hospital

Yoshiaki Yokoi Kishiwada Tokushukai Hospital

Takayuki Ogawa The Jikei University Hospital

Keizo Kimura Social Insurance Kinan Hospital

Mitsuru MunemasaNational Hospital Organization Okayama Medical Center

Hiroaki Mukawa Ogaki Municipal Hospital

Kota Komiyama Tokyo Metropolitan Hiroo Hospital

Takeshi Suzuki Toyokawa City Hospital

Takumi Inoue Hyogo Prefectural Awaji Medical Center

Takafumi Ueno Kurume University Hospital

Teruyasu Sugano Yokohama City University Hospital

Jun Yamashita Tokyo Medical University

Yoshio Yasumura Osaka Police Hospital

Takayuki Ogawa The Jikei University Kashiwa Hospital

Haruo Kamiya Japan Red Cross Nagoya Daiichi Hospital

Hiroshi Fujita Japan Red Cross Kyoto Daini Hospital

Toshiro Shinke Kobe University Hospital

Kazushi Urasawa Tokeidai Memorial Hospital

Shiro Ono Saiseikai Yamaguchi Hospital

Masayoshi Ajioka Tosei General Hospital

Jiro Ando The University of Tokyo Hospital

Koichi Mizuno St. Marianna University School of Medicine Kawasaki Municipal Tama Hospital

Haruo Hirayama Japan Red Cross Nagoya Daini Hospital

Taiki Tojo Kitasato University Hospital

Yuichiro Maekawa Keio University Hospital

Tomohiro Kawasaki Shin Koga Hospital

Takayuki Okamura Yamaguchi University Hospital

Fumitoshi Toyota Chidoribashi Hospital

Yutaka Hikichi, Saga University Hospital

Ichiro Michishita Yokohama Sakae Kyosai Hospital

Takafumi Yagi Daini Okamoto General Hospital

Hiroshi Kamihata Kansai Medical University Hirakata Hospital

Naohisa Shindo Niizashiki Central General Hospital

Nobukazu Ishizaka Osaka Medical College Hospital

Takashi Ashikaga Medical Hospital, Tokyo Medical and Dental University

Yukio Ozaki Fujita Health University Hospital

Hisao HaraNational Center for Global Health and Medicine

Hiroshi Sakamoto Fuji City General Hospital

Kenji Kada, Japan Community Health care Organization: JCHO Chukyo Hospital

Naofumi Doi Nara Prefecture Western Medical Center

Junko Honye Kikuna Memorial Hospital

Hiroyoshi Yokoi Fukuoka Sanno Hospital

Hitoshi Takano Nippon Medical School Hospital

Masahito Kawata Akashi Medical Center

Hidenori Houzawa Ayase Heart Hospital

Toru Ozawa Kobe Rosai Hospital

Arifumi KikuchiNippon Medical School Musashi Kosugi Hospital

Kazushige Kadota Kurashiki Central Hospital

Yoichi Kijima Osaka Saiseikai Nakatsu Hospital

Tomokazu Ikemoto Jichi Medical University Hospital

Yoshihisa Shimada Shiroyama Hospital

Kazuhiko Yumoto Yokohama Rosai Hospital

Kenji Kawajiri Matsubara Tokusyukai Hospital

Yoichi Nozaki Hokko Memorial Hospital

Masayoshi Sakakibara IMS Katsushika Heart Center

Atsushi Tosaka, Kawakita General Hospital

Shigetaka Noma, Saiseikai Utsunomiya Hospital

Yasushi Wakabayashi Seirei Mikatahara General Hospital

Masaharu Okada, Shiga Medical Center for Adults

Mizuki Hirose Meirikai Chuo General Hospital

Yuichiro Takagi KKR Takamatsu Hospital

Takuro Takagi Toshiba General Hospital

Katsumi Miyauchi, Juntendo University Hospital

Kazuhiko Misu,St. Marianna University School of Medicine, The New Toyoko Hospital

Satoshi YasudaNational Cerebral and Cardiovascular Center

Ryohei Yoshikawa Sanda City Hospital

Ichiro InoueHiroshima City Hiroshima Citizens Hospital

Minoru Yoshiyama Osaka City University Hospital

Toru Masuyama, Hyogo College of Medicine Hospital

Yoshiaki Tomobuchi, Seiyu Memorial Hospital

Seiji Yamazaki Sapporo Higashi Tokushukai Hospital

Kengo Tanabe Mitsui Memorial Hospital

Kenji Wagatsuma Toho University Omori Medical Center

Masayuki Kato Maizuru Kyosai Hospital

Kazuya Kawai Chikamori Hospital

Yuji Hamazaki Showa University Hospital

Masakazu Yamagishi Kanazawa University Hospital

Yoshisato Shibata Miyazaki Medical Association Hospital

Kouki Watanabe Saiseikai Matsuyama Hospital

Koichi Tachibana Osaka University Hospital

Hiroshi WadaSaitama Medical Center, Jichi Medical University

Kenji Ninomiya Odawara Cardiovascular Hospital

Hiroshi Suzuki Showa University Fujigaoka Hospital

Jiro Yoshioka Japan Red Cross Nagano Red Cross Hospital

Chikara Mori The Jikei University Daisan Hospital

Masahiro Sonoda National Hospital Organization Kagoshima Medical Center

Toru Kataoka Bell Land General Hospital

Hidenobu Terai Kanazawa Cardiovascular Hospital

Yuko Onishi Hiratsuka Kyosai Hospital

Masanao Toma Hyogo Prefectural Amagasaki Hospital

Takeshi Serikawa Saiseikai Fukuoka General Hospital

Yoritaka Otsuka Fukuoka Wajiro Hospital

Shoji Yano Almeida Memorial Hospital

Soichiro Ebisawa Shinshu University Hospital

Hiroaki Takashima Aichi Medical University Hospital

Hideki Shimomura Fukuoka Tokushukai Medical Center

Yoko Kurumatani Kofu-Kyoritsu Hospital

Shinjo Sonoda,University of Occupational and Environmental Health

Hiroki Uehara Urasoe General Hospital

Study Organization1.1 Executive Committee Members

Masato Nakamura (Toho University, PI)

Hiroyoshi Yokoi (Fukuoka Sanno Hospital, Co-PI）

Junya Ako (Kitasato University）,

Toshiro Shinke (Kobe University)

Raisuke Iijima (Toho University)

1.2 Advisory Committee

Shigeru Saito (Shonan Kamakura General Hospital)

Shinsuke Nanto (Nishinomiya Municipal Hospital)

Kazuaki Mitsudo (Kurashiki Central Hospital)

1.３ Independent Data Monitoring Committee

(DMC)

Chairman:

Tetsu Yamaguchi (Toranomon Hospital)

Voting Members:

Takaaki Isshiki (Ageo Central General Hospital)

Hiroyuki Daida (Juntendo University Hospital)

Masakatsu Nishikawa (Mie University Hospital)

1.4 Clinical Events Committee

Adjudicators – Interventional Cardiology

Tadanori Aizawa (The Cardiovascular Institute)

Ryuta Asano (Asano Cardiovascular Clinic)

Akira Yamashina (Tokyo Medical University Hospital)

Adjudicators – Neurology

Yasushi Okada (National Organization Kyushu Medical

Center)

Adjudicators – Gastroenterological

Takashi Kawai (Tokyo Medical University Hospital)

1.5 Statisticians Responsible for Final Analysis

Toshimitsu Hamasaki (National Cerebral and

Cardiovascular Center)

1.6 Data Coordination

Data Management: Bel system

IRT/IWT Services: Cenduit, Durham, NC, US

Web-based Data Capture: Oracle Health Sciences,

Boston, MA, US

Thank you for your attention