Shinya Goto, Masatsugu Hori, Norio Tanahashi,

Michael Hanna, Suzuko Oikawa, John Alexander

ARISTOTLE Japan investigators

Sponsored by Bristol-Myers Squibb and Pfizer

Apixaban versus Warfarin in Patients with Atrial Fibrillation -Sub-Analysis in Japanese Patients-

①　Consultation fees:　　　　　　 EISAI　　　　　 ②　Stock ownership/profit:　　　　　　　 　none ③　Patent fees:　　　　　　　　　　 　 none ④　Remuneration for lecture:　　　 EISAI, Sanofi-Aventis, Otsuka ⑤　Manuscript fees:　　　　　　　　 none ⑥　Trust research/joint research funds: Sanofi-Aventi, Eisai, 　　　　　 　　　　　　　　　　　　 Berlinger-Ingelheim, Otsuka ⑦　Scholarship fund:　　　 　　　　 none ⑧　Affiliation with Endowed Department: none 　　 ⑨　Other remuneration such as gifts: none

The Japanese Circulation Society

COI Disclosure 　

Shinya Goto

Background - Japan sub-analysis -

• Warfarin is highly effective in stroke prevention with atrial fibrillation, but has several limitations.

•  ARISTOTLE study demonstrated that….. Apixaban is Superior to warfarin at preventing Stroke/SE, Causes less Bleeding, and Results lower Mortality.

•  Sub-analysis was performed for Japanese AF patients in

the ARISTOTLE study

Warfarin (target INR 2-3)

Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients)

Primary outcome: stroke or systemic embolism

Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

Randomize double blind,

double dummy (n = 18,201)

Inclusion risk factors   Age ≥ 75 years   Prior stroke, TIA, or SE   HF or LVEF ≤ 40%   Diabetes mellitus   Hypertension

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

Dose reduction criteria: At least 2 of following risks   Age ≥ 80 years   Body weight ≤ 60 kg   S-Creatinine ≥ 1.5mg/dL

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke

Japan Global

Patient enrollment Feb. 2008 ~Sep. 2009

Dec. 2006 ~ Apr. 2010

TTR (INR 2-3), (median) [%] 67.0% 66.0%

Duration of follow-up (median) [years] 2.1 years 1.8 years

Drug discontinuation - Apixaban 18.0% 25.3%

Drug discontinuation - Warfarin 30.3% 27.5%

Lack of vital status at the end of trial, N (%) 0 (0%) 380 (2.1%)

　　Withdrawal of consent, N 0 199

　　Loss to follow-up, N 0 69

Trial Metrics

Baseline Characteristics Japan Global

Characteristic Apixaban　N=161

Warfarin　N=175

Apixaban　N=9120

Warfarin　N=9081

Age, median 71 70 70 70 Women, % 22 21 35 35 CHADS2, mean 2.0 2.0 2.1 2.1

1, % 42 40 34 34 2, % 26 31 36 36 ≥ 3, % 32 28 30 30

Risk factors, % Age ≥75 yrs 33 34 31 31 Prior stroke, TIA, SE 25 27 19 20 Heart failure or reduced LV EF 18 23 35 36 Diabetes 29 21 25 25 Hypertension 78 76 87 88

Renal function (ClCr ml/min), % Normal (>80) 22 17 41 41 Mild impairment (>50 – 80) 53 58 42 42 Moderate impairment (>30 – 50) 23 23 15 15 Severe impairment (≤ 30) 2.5 2.3 1.5 1.5

Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011

No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768

P (non-inferiority)<0.001 21% RRR

Efficacy　 Japan vs. Global

Efficacy Outcome　(ITT)

Japan Global Event Rate (%/yr) Event Rate (%/yr)

HR (95% CI) P Value Apixaban Warfarin Apixaban Warfarin N=161 N=175 N=9120 N=9081

Stroke or systemic embolism 　 0.87 　 1.67 　 1.27 　 1.60 　0.79 (0.66, 0.95) 　 0.011

Stroke 　 0.87 　 1.67 　 1.19 　 1.51 　0.79 (0.65, 0.95) 　 0.012

Ischemic or uncertain 　 0.87 　 1.11 　 0.97 　 1.05 　0.92 (0.74, 1.13) 　 0.42

Hemorrhagic 　 0 　 0.55 　 0.24 　 0.47 　0.51 (0.35, 0.75) < 0.001

Systemic embolism (SE) 　 0 　 0 　 0.09 　 0.10 　0.87 (0.44, 1.75) 　 0.70

All-cause death 　 1.74 　 3.02 　 　 3.52 　 3.94 　0.89 (0.80, 0.998) 　 0.047

Stroke, SE, or all-cause death   　 2.62 　 3.90 　 　 4.49 　 5.04 　0.89 (0.81, 0.98) 　 0.019

MI   　 0 　 0.28 　 0.53 　 0.61 　0.88 (0.66, 1.17) 0.37

Major Bleeding ISTH definition

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001

No. at Risk Apixaban 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491

31% RRR

Bleeding Japan vs. Global

Outcome

Japan Global Event Rate (%/yr) Event Rate (%/yr)

HR (95% CI) P Value Apixaban Warfarin Apixaban Warfarin N=160 N=175 N=9120 N=9081

Primary safety outcome: ISTH major bleeding 　 1.26 　 5.99 　 2.13 　 3.09 　 0.69 (0.60, 0.80) <　 0.001

Intracranial 　 0 　 1.97 　 0.33 　 0.80 　 0.42 (0.30, 0.58) <　 0.001

Gastrointestinal 　 0.63 　 1.97 　 0.76 　 0.86 　 0.89 (0.70, 1.15) 　 0.37 Major or clinically relevant non-major bleeding 　 1.90 　 7.86 　 4.07 　 6.01 　 0.68 (0.61, 0.75) < 0.001

GUSTO severe bleeding 　 0 　 2.63 　 0.52 　 1.13 　 0.46 (0.35, 0.60) <　 0.001

TIMI major bleeding 0.31 2.97 0.96 1.69 0.57 (0.46, 0.70) < 0.001 Any bleeding 20.95 40.13 18.1 25.8 0.71 (0.68, 0.75 < 0.001

Kaplan–Meier Plot for All Bleeding Subjects treated in Japan

Apixaban 51 patients, 20.95% per year Warfarin 82 patients, 40.13% per year HR 0.60 (95% CI, 0.42-0.85)

0.00

0.60

0.24

0.12

0.36

Prop

ortio

n of

Sub

ject

s

with

All

Ble

edin

g

0.48 0.54

0.18

0.06

0.30

0.42

0

Time to All Bleeding (months) 6 9 12 18 24 3 30 27 21 15

Apixaban

Warfarin

Adverse Events and Liver Function Tests

N (%) Japan Global

Apixaban Warfarin Apixaban Warfarin N=160 N=175 N=9088 N=9052

Total patients with an adverse event 154 (96.3) 169(96.6) 7406 (81.5) 7521 (83.1)

Total patients with a serious adverse event 51(31.9) 60(34.3) 3182 (35.0) 3302 (36.5)

Serious adverse events reported in ≥ 1% of patients in either treatment group    

Atrial fibrillation 0 2(1.1) 301 (3.3) 287 (3.2) Pneumonia 2 (1.3) 6(3.4) 202 (2.2) 231 (2.6)

Discontinuations due to an adverse event 17 (10.6) 30(17.1) 688 (7.6) 758 (8.4)

ALT or AST > 3X ULN & total bilirubin > 2X ULN 0/158 0/175 30/ 8788 (0.3) 31/ 8756 (0.4)

ALT elevation    

> 3X ULN 2/158 (1.3) 3/175 (1.7) 100/ 8790 (1.1) 89/ 8759 (1.0)

> 5X ULN 2/158 (1.3) 2/175 (1.1) 45/ 8790 (0.5) 47/ 8759 (0.5)

> 10X ULN 0/158 2/175 (1.1) 16/ 8790 (0.2) 20/ 8759 (0.2)

> 20X ULN 0/158 1/175 (0.6) 8/ 8790 (<0.1) 12/ 8759 (0.1)

Conclusion

In patients with atrial fibrillation, apixaban is

superior to warfarin at preventing stroke or

systemic embolism, causes less bleeding, and

results in lower mortality.

Japan:

The results in Japan are consistent with those of the

global.

THANKS to all Japan Collaborators National Coordinator — Shinya Goto :Tokai University School of Medicine

Japan　Safety Review　Group — Masatsugu Hori :Osaka Medical Center for Cancer & Cardiovascular Diseases　　　　 　Norio Tanahashi : Saitama Medical University International Medical Center John Alexander : Duke University Medical Center

Investigator — Fukui General Clinic Kazuo Satake, Mayumi Taniguchi, Kihara Cardiovascular Clinic Hajime Kihara, Azusa Kitano, National Hospital Organization Takasaki General Medical Center　Toyoshi Sakaki,Yoshiko Murayama, Takagi Hospital Takeshi Yoshihiro, Akiko Tsubakihara, Hokusetsu General Hospital Michihiro Suwa, Yukiko Ohara, Izumi General Hospital Hiroshi Yoshii, Yukie Nakama, Oita Red Closs Hospital Tetsu Iwao, Sayumi Sakaguchi, Shuwa General Hospital Susumu Adachi, Takahiro Tojo, Nagasaki University Hospital Kouji Maemura, Yayoi Yoshioka, Saga University Hospital Kouichi Node, Mayumi tomiyasu,　Medical Corp. Sakura-kai Takahashi Hospital Akihiko Takahashi, Toshiomi Kunihiro, Toyama Prefectural Central Hospital Kazuo Usuda, Naomi Tamura,　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　Otofuke Koumeikan Hospital Kouichi Fujii, Mika　Ohshima,　　　　　　Sapporo Yuushokan Hospital Hiroyuki Takagi, Minori Matsuo, National Hospital Organization Osaka National Hospital Yukihiro Koretsune, Tomoko Kitagawa, Tomakomai

Nisshou Hospital Shigeki Yura, Masato Fujimori, Osaka Saiseikai Izuo Hospital Satoshi Yamamoto, Yukako

Sawada, Izumi Municipal Hospital Yoshio Kawase Hatsumi Watanabe, Nakamura Cardiovascular Clinic Yuuichiro Nakamura, Kazumi Yamamoto, Nara City Hospital Akihiko Matsushima, Mayumi Hyakken,　Toho University Ohashi Medical Center Kaoru Sugi, Etsuko Nagumo, Saga Prefectural Hospital KOSEIKAN Kiyoshi Hayashida, Rie Yamaguchi, Osaka General Medical Center Takahisa Yamada, Noriko Oyama, Showa University Hospital Youichi Kobayashi, Fumiyo Hibino, Tokyo Metropolitan Geriatric Hospital Yuusuke Tsubokou, Kaoru Fujinami, National Hospital Organization Yokohama Medical Center Kazunori Iwade, Yuuko Sakuma, Showa University Fujigaoka Hospital Yuukei Higashi, Kanae Iwata, Yubari Medial Center Tomohiko Murakami, Aya Kumagai, National Cerebral and Cardiovascular Center Shirou Kamakura, Fujiko Nakahara, National Hospital Oraniztion Sendai Medical Center Tsuyoshi Shinozaki, Mitsuo Yata, Kurume University Medical Center Hisao Ikeda, Kiyoko Tanaka, Tokai University Hospital Shinya Goto, Michiyo Iwamoto, Medical Corporation Tenyokai Central Clinic Yoshihiko Atsuchi, Narumi Otsuka, Ishinkaii Yao General Clinic Syouzo Tanaka, Yukari Toyama, Iwakuni Medical Center Takayuki Hisaoka, Kunihiro Toshiomi, Uzumasa Hospital Masashi Yamashita, Yukako Sawada, Saga Memorial Hospital Kenichi Yamamoto, Rie Yamaguchi, Yokosuka General Hospital Uwamachi Takamasa Iwasawa, Yuka Motegi, Iseikai Hospital Hirotaka Murata, Yasunori Yamaguchi, Shirakawa Kosei General Hospital Tomiyoshi Saito, Mieko Ishii