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