Real world evidence in Practical consideration for data collection and use

Junya Ako, MD

Professor, Cardiovascular Medicine Kitasato University, Kanagawa, Japan Junya Ako, MD

Speaking honoraria: Terumo, Bayer, Sanofi Real world data in Japan • Registries – Investigator initiated – Scientific society initiated – PMS • Claims data based Real world data Registries • Investigator initiated registries – Disease specific • CREDO- (PCI, CABG) • KICS (PCI) • J-MINUET (Universal definition MI) • OCEAN TAVI J-MINUET study Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition

3,283 consecutive patients with acute MI diagnosed by universal definition (type 1 or 2) within 48 hours of symptom in 28 Japanese institutions between 2012.7-2014.3

1 Medical University 2 Medical Center 3 Dokkyo Medical University 4 Medical Center Jichi Medical University 5 Gunma Prefectural Cardiovascular Center 6 Nippon Medical School 3,283 patients with MI 7 Teikyo University 8 Mitsui Memorial Hospital 9 Sakakibara Heart Institut 10 City University Medical Center Ishihara M, et al. Circ J 2017; 81: 958-965 11 Suwa Red Cross Hospital 12 Juntendo University Hospital ST-elevation 13 Fujita Health University 14 Ogaki Municipal Hospital (+) (-) 15 National Cerebral and Cardiovascular Center 16 General Medical Center 17 Sakurabashi Watanabe Hospital 18 Medical University 19 Kansai Rosai Hospital 20 The Sakakibara Heart Institute of 1,021 patients with NSTEMI 21 22 City Hospital 23 University 24 University 25 Saiseikai Kumamoto Hospital CK elevation 26 Kumamoto Medical Center (+) (-) 27 Medical Association Hospital 28 Okinawa Chubu Hospital STEMI NSTEMI+CK NSTEMI-CK (n=2,262) (n=563) (n=458) J-MINUET study Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition

Primary Endpoint 50 STEMI P<0.001 NSTEMI+CK 40 NSTEMI-CK

30

20

10 Cumulative Incidence (%) Incidence Cumulative

Death, MI, Stroke, Cardiac 0 failure, Revasc. ｆor UA 0 365 730 1095 Days after MI J-MINUET study Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition

1. Ishihara M, Fujino M, Ogawa H, Yasuda S, Noguchi T, Nakao K, Ozaki Y, Kimura K, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Tsujita K, Nishimura K, Miyamoto Y; J-MINUET investigators. Clinical presentation, management and outcome of Japanese patients with acute myocardial infarction in the troponin era - Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET). Circ J 2015; 79: 1255-1262. 2. Ishihara M, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Fujino M, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Hirata K, Tanabe K, Shibata Y, Owa M, Tsujita K, Funayama H, Kokubu N, Kozuma K, Tobaru T, Oshima S, Nakai M, Nishimura K, Miyamoto Y, Ogawa H; J-MINUET Investigators. Long-term outcomes of non-ST-elevation myocardial infarction without creatine kinase elevation - The J-MINUET Study. Circ J 2017; 81: 958-965. 3. Kuji S, Kosuge M, Kimura K, Nakao K, Ozaki Y, Ako J, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Nishimura K, Miyamoto Y, Ishihara M; J-MINUET Investigators. Impact of acute kidney injury on in-hospital outcomes of patients with acute myocardial infarction - results from the Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET) substudy. Circ J 2017; 81: 733-739. 4. Fujino M, Ishihara M, Ogawa H, Nakao K, Yasuda S, Noguchi T, Ozaki Y, Kimura K, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Ako J, Nakai M, Nishimura K, Miyamoto Y; J-MINUET Investigators. Impact of symptom presentation on in-hospital outcomes in patients with acute myocardial infarction. J Cardiol 2017; 70: 29-34. 5. Ogita M, Suwa S, Ebina H, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Fujino M, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Hirata K, Tanabe K, Shibata Y, Owa M, Hokimoto S, Funayama H, Kokubu N, Uemura S, Kozuma K, Tobaru T, Saku K, Oshima S, Nishimura K, Miyamoto Y, Ishihara M; J-MINUET Investigators. Off-hours presentation does not affect in-hospital mortality of Japanese patients with acute myocardial infarction: J-MINUET substudy. J Cardiol 2017; 70: 553-558. 6. Horiuchi Y, Aoki J, Tanabe K, Nakao K, Ozaki Y, Kimura K, Ako J, Yasuda S, Noguchi T, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Hirata K, Shibata Y, Nishimura K, Miyamoto Y, Ishihara M; J-MINUET Investigators. A high level of blood urea nitrogen is a significant predictor for in-hospital mortality in patients with acute myocardial infarction. Int Heart J 2018; 59: 263-271. 7. Hashimoto T, Ako J, Nakao K, Ozaki Y, Kimura K, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Hirata K, Tanabe K, Shibata Y, Owa M, Tsujita K, Funayama H, Kokubu N, Kozuma K, Uemura S, Tobaru T, Saku K, Oshima S, Nakai M, Nishimura K, Miyamoto Y, Ogawa H, Ishihara M; J-MINUET Investigators. A lower eicosapentaenoic acid/arachidonic acid ratio is associated with in-hospital fatal arrhythmic events in patients with acuteIssues: myocardial infarction: aFunding. J-MINUET substudy. Heart Vessels 2018; 33: 481-488. 8. Hashimoto T, Ako J, Nakao K, Ozaki Y, Kimura K, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Hirata K, Tanabe K, Shibata Y, Owa M, Tsujita K, Funayama H, Kokubu N, Kozuma K, Uemura S, Tobaru T, Saku K, Oshima S, Nakai M, Nishimura K, Miyamoto Y, Ogawa H, Ishihara M; J-MINUET Investigators. Pre-procedural Thrombolysis In Myocardial Infarction flow in patients with ST- segment elevation myocardial infarction: A J-MINUET substudy. Int HeartDependent J 2018; 59: 920-925. on investigators’ enthusiasm. 9. Okura H, Saito Y, Soeda T, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Hirohata A, Morita Y, Inoue T, Okamura A, Uematsu M, Hirata K, Tanabe K, Shibata Y, Owa M, Tsujita K, Nishimura K, Miyamoto Y, Ishihara M; J-MINUET investigators. Frequency and prognostic impact of intravascular imaging-guided urgent percutaneous coronary intervention in patients with acute myocardial infarction: results from J-MINUET. Heart Vessels 2019; 34: 564-571. 10. Okuno T, Aoki J, Tanabe K, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Mano T, Hirata K, Shibata Y, Owa M, Tsujita K, Funayama H, Kokubu N, Kozuma K, Uemura S, Tobaru T, Saku K, Ohshima S, Nishimura K, Miyamoto Y, Ogawa H, Ishihara M; J-MINUET investigators. Admission heart rate is a determinant of effectiveness of beta-blockers in acute myocardial infarction patients. Circ J 2019; 83: 1054-1063. 11. Okuno T, Aoki J, Tanabe K, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Yasuda S, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Mano T, Hirata K, Shibata Y, Owa M, Tsujita K, Funayama H, Kokubu N, Kozuma K, Uemura S, Tobaru T, Saku K, Ohshima S, Nishimura K, Miyamoto Y, Ogawa H, Ishihara M; J-MINUET investigators. Association of onset-season with characteristics and long-term outcomes in acute myocardial infarction patients: results from the Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET) substudy. Heart Vessels 2019; 34: 899-1908. 12. Oikawa J, Fukaya H, Ako J, Nakao K, Ozaki Y, Kimura K, Noguchi T, Suwa S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Mano T, Miyamoto Y, Ogawa H, Ishihara M; J-MINUET investigators. Risk factors of in-hospital lethal arrhythmia following acute myocardial infarction in patients undergoing primary percutaneous coronary intervention - Insight from the J-MINUET study -. Circ Rep 2019 Dec 27. [Epub ahead of print] 13. Wada H, Ogita M, Suwa T, Nakao K, Ozaki Y, Kimura K, Ako J, Noguchi T, Yasuda S, Fujimoto K, Nakama Y, Morita T, Shimizu W, Saito Y, Hirohata A, Morita Y, Inoue T, Okamura A, Mano T, Hirata K, Tanabe K, Shibata Y, Owa M, Tsujita K, Funayama H, Kokubu N, Kozuma K, Uemura S, Tobaru T, Saku K, Ohshima S, Nishimura K, Miyamoto Y, Ogawa H, Ishihara M; J-MINUET investigators. Guideline adherence and long-term clinical outcomes in patients with acute myocardial infarction: a Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) substudy. Eur Heart J Acute Cardiovasc Care (in press) EXPLORE-J

Detailed Lipid profile. 2.7% FH among ACS patients Sanofi funded. 59sites, 1944 pts Atherosclerosis 277 (2018) 362e368 EXPAND: rivaroxaban Japanese dose

684 sites, 7141 pts Bayer partly funded. Complementary to J-ROCKET Using Japanese (reduced dose) rivaroxaban Int J Cardiol 2018;258:126-32.

Issues: Selection bias. possible COI. Real world data Registries • Scientific society initiated – Disease specific • J-PCI Board/institution Certification • J-EVT/SHD Publications from J-PCI

JACC Card Interv 2017;10:918-927 Circ Cardiovasc Interv 2016;9: pii:e004278.

JAHA 2019;8:e011183. AJC 2017;119:872-880. Issues: Growing number of registries NO financial incentive for sites Real world data in Japan • Registries – Investigator initiated – Scientific society initiated – PMS Necessary for Tx not particularly suitable for randomized trials, • Claims data based Impella PMS Participated Sites and Patient Enrollment 109 sites participated 1,230 Patients enrolled in J-PVAD registry since Oct. 2017 – Dec. 2019 (Jan.2020) Cumulative # of patients and # of Locked CRFs

Supposed to be presented at JCS 2020. J-PVAD registry • Led by IMPELLA committee (Group of delegates from 10 scientific societies) • All patients treated by IMPELLA should be enrolled into Registry (institution certification) • Follow up: 30days post Impella explant

Collaboration for Appropriate use of IMPELLA

PMS Hospitals

Generating Real-World Evidence EDC Real world evidence matters

JAMA. doi:10.1001/jama.2020.0254 PMS Post conditional approval • In 2015, PMDA gave fast-track approval for HEART-SHEET, autologous myoblast transplant, for the treatment of severe ischemic cardiomyopathy. On a condition that the therapy is compared with a non-randomized cohort of heart failure patients.

Heart sheet 60pts Propensity match Comparison Control HF 120 pts Still Ongoing Real world data in Japan • Registries – Investigator initiated – Scientific society initiated – PMS • Claims data based The Japanese Registry Of All cardiac and vascular Diseases (JROAD) ; Collaboration between JCS and National Cerebral and Cardiovascular Center

Japanese Circulation Society

JCS NCVC

• The JCS initiated JROAD in 2004 by the JCS and collects data from all teaching hospitals with cardiovascular beds (N=1,353 in 2017 data). • JROAD derives the data from DPC data (Japanese equivalent of DRG payment). 2017 Survey Institute, n registered, n Response,% Training hospitals (TH) 1,017 1,017 100％ Associated hospitals (AH) 336 336 100％ Total 1,353 1,353 100％ JROAD Increasing number of HF admission

Pt no. (A) AMI Mortality Pt no. (B) HF Mortality 100,000 10.0% 300,000 10.0% 7.9% 90,000 8.6% 8.5% 9.0% 7.9% 9.0% 8.4% 8.3% 8.3% 7.8% 260,157 8.0% 8.2% 250,000 238,840 247,996 80,000 8.0% 229,417 8.0% 73,421 69,219 67,918 71,803 212,739 70,000 68,850 7.0% 7.0% 200,000 60,000 6.0% 6.0%

50,000 5.0% 150,000 5.0%

40,000 4.0% 4.0% 100,000 30,000 3.0% 3.0%

20,000 2.0% 2.0% 50,000 10,000 1.0% 1.0%

0 0.0% 0 0.0% 2013 2014 2015 2016 2017 2013 2014 2015 2016 2017 Yasuda S, Ogawa H, et al. Circulation 2018; 138: 965-967 JROAD GDMT and in hospital mortality

J Am Heart Assoc. 2019;8:e009692. DOI: 10.1161/JAHA.118. 009692. International comparison CVD-REAL 2 International comparison CVD-REAL 2

Background differences Difficult data processing/interpretation Real world evidence in Japan Practical consideration for data collection and use • In CVD area, real world data in Japan range from registries to claims activities, complementing those of randomized clinical trials. • Future directions include use of electronic health records and patient-generated data.