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Impact of the Beta-1 Adrenergic Receptor Polymorphism on Tolerability and Efficacy of Bisoprolol Therapy in Heart Failure Patients
The 18th Annual Scientific Meeting Table. Baseline clinical characteristics, and 2-year clinical outcomes
Variable, n (%) Gender (Male) STEMI CKD 2-year clinical outcomes (%) Total MACE Cardiac death Non cardiac death Myocardial infarction TVR (Target Vessel Revascularization) In-hospital outcomes (%) All death Cardiac death 2-year clinical outcomes except In-hospital death (%) Total MACE Cardiac death Non cardiac death Myocardial infarction TVR
LVEF$40% (n5279)
LVEF!40% (n5185)
205 (73.4) 150 (53.7) 6 (2.15) n5250
117 (63.2) 132 (71.3) 10 (5.40) n5148
50 8 5 7 34
(19.7) (3.14) (1.96) (2.75) (13.3)
44 19 5 5 18
(27.2) (11.7) (3.08) (3.08) (11.1)
n5279
n5185
4 (1.43) 4 (1.43) n5250
14 (7.56) 13 (7.02) n5148
P P value value * 0.019 0.000 0.060
0.075 0.001 0.468 0.844 0.494
0.001 0.002
0.099* 0.005*
JHFS
S201
1) At position 389 of the beta-1 adrenergic receptor (ADRB1), the observed minor Gly allele frequency was 21% and no deviation from Hardy-Weinberg equilibrium was seen in the genotypic distribution of Arg389Gly (p50.75). 2) There was no significant difference in the final heart rate across the genotypes. However, Arg389Arg genotype group required significantly larger amount of bisoprolol compared with Gly389X (Gly389Arg+Gly389Gly) group in order to achieve the same level of heart rate reduction (5.2662.62 mg vs 3.9662.05mg, p50.022). 3) There were no significant differences either in LVEF or in left ventricular enddiastolic volume between Arg389Arg genotype group and Gly389X group. There was also no significant difference in exercise capacity or B-natriuretic peptide level change between two groups. 4) However, interestingly, there was two-fold higher rate of readmission (21.2% vs 10.0%, p50.162) and one heart-failure related death in Arg389Arg group. Conclusion: In heart failure patients, ABRB1 Gly389X genotype showed greater response to bisoprolol than Arg389Arg genotype. ABRB1 Gly389X genotype was also suggested to have better prognosis than Arg389Arg genotype. The findings of this study implicate the potential of individually tailoring of beta-blocker therapy according to genotypes.
0.002*
P-085 46 4 5 7 34
(18.4) (1.6) (2) (2.8) (13.6)
30 7 3 4 18
(20.2) (4.72) (2.02) (2.70) (12.1)
0.646 0.066 0.985 0.954 0.681
0.131*
Design Challenges for Heart Failure Prevention Clinical Trials: Adaptive Design Approach TOSHIMITSU HAMASAKI1,2, ATSUSHI NAKANO3, KANAE TAKAHASHI1, HIDEAKI KANZAKI4, MASANORI ASAKURA3, MASAFUMI KITAKAZE3 1 Department of Advanced Medical Technology Development, National Cerebral and Cardiovascular Center, 2Department of Innovative Clinical Trials and Data Science, Osaka University Graduate School of Medicine, 3Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, 4Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center Cardiovascular prevention clinical trials generally require a large number of subjects and long-term follow-up period to observe events of interest to evaluate the risk and benefit of a test intervention compared with any control intervention. These may increase difficulties in conducting and managing clinical trials with respect to resources such as time and cost. One recent major advance in clinical trial methodology is adaptive designs. Adaptive designs allow for smaller, shorter trials while ensuring scienti:fic rigor and integrity of results. Adaptive designs offer the opportunities of saving resources and preventing subjects from being exposed to an ineffective intervention unnecessarily. However, along with these benefits, adaptive designs introduce additional challenges: decision complexity, statistical expertise and operational demands. Accumulated experiences are required for a practical use of adaptive designs for clinical trials, especially for cardiovascular prevention clinical trials. In this presentation, we will share our lessons learned in planning and designing “linical Study of the Effect of Teneligliptin on the Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes Mellitus” (TOPLEVEL Study). As adaptive features, the study design allows to assess either futility or efficacy of the test intervention, and to recalculate the sample size based on the observed effect at the interim. We discuss the advantages and disadvantages of adaptive designs in heart failure prevention clinical trials.
Figure. Kaplan-Meiyer curve showed that there was no significant difference in cardiac death between two groups during 2-year clinical follow-up period except in-hospital mortality.
P-083 Impact of the Beta-1 Adrenergic Receptor Polymorphism on Tolerability and Efficacy of Bisoprolol Therapy in Heart Failure Patients HAE-YOUNG LEE1, WOOK-JIN CHUNG2, HUI-KYUNG JEON3, HONG-SEOG SEO4, DONG-JU CHOI5, EUN-SEOK JEON6, JAE-JOONG KIM7, JOON HAN SHIN8, SEOK-MIN KANG9, SUNG CIL LIM10, SANG-HONG BAEK11 1 Seoul National University Hospital, 2Gachon University Gill Hospital, 3Catholic University Uijeongbu St. Mary’s Hospital, 4Korea University Guro Hospital, 5 Seoul National University Bundang hospital, 6Samsung Medical Center, 7Asan Medical Center, 8Ajou University Hospital, 9Severance hospital of Yonsei University, 10Catholic College of Pharmacy, Catholic University of Korea, 11 Catholic University Seoul St. Mary’s Hospital Objectives: The association between the coding region variations of adrenergic receptor signaling genes and therapeutic effect were investigated in heart failure patients. Methods: Genotypic analysis was carried out in 83 patients of chronic heart failure patients (NYHA class II-III) with reduced left ventricular ejection fraction (LVEF) ! 45%. Enrolled patients started bisoprolol 1.25mg once daily, up-titrated to the maximally tolerable dose, then maintained until 1 year of treatment. Results:
P-086 Long-term Prognosis in Patients Treated With Cardiac Resynchronization Therapy REISUKE YOSHIZAWA1, TOMONORI ITOH1, YOSHIHIRO SATOH2, SATOSHI NAKAJIMA1, MAHITO OZAWA2, FUSANORI KUNUGITA2, TAKASHI KOMATSU2, MOTOYUKI NAKAMURA2, YOSHIHIRO MORINO1 1 Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan, 2Division of Cardioangiology, Nephrology and Endocrinology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan Background: The effect of cardiac resynchronization therapy (CRT) is controversial for long-term prognosis in patients with severe heart failure in the previous study. Objectives: To clarify long-term prognosis in patients treated with CRT. Methods: The subjects were 24 consecutive CRT patients admitted to our institute from 2006 to 2014 (21 males and 3 females). We retrospectively evaluated patient characteristics and electrocardiogram just before and after CRT implanted. Cardiac events were defined as heart failure requiring hospitalization/death from cardiovascular events. Results: Average age at CRT implantation was 60614 years in the study patients. Basal heart disease were as follows: dilated cardiomyopathy 15, ischemic heart disease 3, and the others 6. Average BNP level before CRT implantation decreased to after CRT implantation (8206676 pg/ml to 5876771 pg/ml; p50.206). However, QRS widths just before and after CRT implantation were 150627 and 146622
Variable, n (%) Gender (Male) STEMI CKD 2-year clinical outcomes (%) Total MACE Cardiac death Non cardiac death Myocardial infarction TVR (Target Vessel Revascularization) In-hospital outcomes (%) All death Cardiac death 2-year clinical outcomes except In-hospital death (%) Total MACE Cardiac death Non cardiac death Myocardial infarction TVR
LVEF$40% (n5279)
LVEF!40% (n5185)
205 (73.4) 150 (53.7) 6 (2.15) n5250
117 (63.2) 132 (71.3) 10 (5.40) n5148
50 8 5 7 34
(19.7) (3.14) (1.96) (2.75) (13.3)
44 19 5 5 18
(27.2) (11.7) (3.08) (3.08) (11.1)
n5279
n5185
4 (1.43) 4 (1.43) n5250
14 (7.56) 13 (7.02) n5148
P P value value * 0.019 0.000 0.060
0.075 0.001 0.468 0.844 0.494
0.001 0.002
0.099* 0.005*
JHFS
S201
1) At position 389 of the beta-1 adrenergic receptor (ADRB1), the observed minor Gly allele frequency was 21% and no deviation from Hardy-Weinberg equilibrium was seen in the genotypic distribution of Arg389Gly (p50.75). 2) There was no significant difference in the final heart rate across the genotypes. However, Arg389Arg genotype group required significantly larger amount of bisoprolol compared with Gly389X (Gly389Arg+Gly389Gly) group in order to achieve the same level of heart rate reduction (5.2662.62 mg vs 3.9662.05mg, p50.022). 3) There were no significant differences either in LVEF or in left ventricular enddiastolic volume between Arg389Arg genotype group and Gly389X group. There was also no significant difference in exercise capacity or B-natriuretic peptide level change between two groups. 4) However, interestingly, there was two-fold higher rate of readmission (21.2% vs 10.0%, p50.162) and one heart-failure related death in Arg389Arg group. Conclusion: In heart failure patients, ABRB1 Gly389X genotype showed greater response to bisoprolol than Arg389Arg genotype. ABRB1 Gly389X genotype was also suggested to have better prognosis than Arg389Arg genotype. The findings of this study implicate the potential of individually tailoring of beta-blocker therapy according to genotypes.
0.002*
P-085 46 4 5 7 34
(18.4) (1.6) (2) (2.8) (13.6)
30 7 3 4 18
(20.2) (4.72) (2.02) (2.70) (12.1)
0.646 0.066 0.985 0.954 0.681
0.131*
Design Challenges for Heart Failure Prevention Clinical Trials: Adaptive Design Approach TOSHIMITSU HAMASAKI1,2, ATSUSHI NAKANO3, KANAE TAKAHASHI1, HIDEAKI KANZAKI4, MASANORI ASAKURA3, MASAFUMI KITAKAZE3 1 Department of Advanced Medical Technology Development, National Cerebral and Cardiovascular Center, 2Department of Innovative Clinical Trials and Data Science, Osaka University Graduate School of Medicine, 3Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, 4Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center Cardiovascular prevention clinical trials generally require a large number of subjects and long-term follow-up period to observe events of interest to evaluate the risk and benefit of a test intervention compared with any control intervention. These may increase difficulties in conducting and managing clinical trials with respect to resources such as time and cost. One recent major advance in clinical trial methodology is adaptive designs. Adaptive designs allow for smaller, shorter trials while ensuring scienti:fic rigor and integrity of results. Adaptive designs offer the opportunities of saving resources and preventing subjects from being exposed to an ineffective intervention unnecessarily. However, along with these benefits, adaptive designs introduce additional challenges: decision complexity, statistical expertise and operational demands. Accumulated experiences are required for a practical use of adaptive designs for clinical trials, especially for cardiovascular prevention clinical trials. In this presentation, we will share our lessons learned in planning and designing “linical Study of the Effect of Teneligliptin on the Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes Mellitus” (TOPLEVEL Study). As adaptive features, the study design allows to assess either futility or efficacy of the test intervention, and to recalculate the sample size based on the observed effect at the interim. We discuss the advantages and disadvantages of adaptive designs in heart failure prevention clinical trials.
Figure. Kaplan-Meiyer curve showed that there was no significant difference in cardiac death between two groups during 2-year clinical follow-up period except in-hospital mortality.
P-083 Impact of the Beta-1 Adrenergic Receptor Polymorphism on Tolerability and Efficacy of Bisoprolol Therapy in Heart Failure Patients HAE-YOUNG LEE1, WOOK-JIN CHUNG2, HUI-KYUNG JEON3, HONG-SEOG SEO4, DONG-JU CHOI5, EUN-SEOK JEON6, JAE-JOONG KIM7, JOON HAN SHIN8, SEOK-MIN KANG9, SUNG CIL LIM10, SANG-HONG BAEK11 1 Seoul National University Hospital, 2Gachon University Gill Hospital, 3Catholic University Uijeongbu St. Mary’s Hospital, 4Korea University Guro Hospital, 5 Seoul National University Bundang hospital, 6Samsung Medical Center, 7Asan Medical Center, 8Ajou University Hospital, 9Severance hospital of Yonsei University, 10Catholic College of Pharmacy, Catholic University of Korea, 11 Catholic University Seoul St. Mary’s Hospital Objectives: The association between the coding region variations of adrenergic receptor signaling genes and therapeutic effect were investigated in heart failure patients. Methods: Genotypic analysis was carried out in 83 patients of chronic heart failure patients (NYHA class II-III) with reduced left ventricular ejection fraction (LVEF) ! 45%. Enrolled patients started bisoprolol 1.25mg once daily, up-titrated to the maximally tolerable dose, then maintained until 1 year of treatment. Results:
P-086 Long-term Prognosis in Patients Treated With Cardiac Resynchronization Therapy REISUKE YOSHIZAWA1, TOMONORI ITOH1, YOSHIHIRO SATOH2, SATOSHI NAKAJIMA1, MAHITO OZAWA2, FUSANORI KUNUGITA2, TAKASHI KOMATSU2, MOTOYUKI NAKAMURA2, YOSHIHIRO MORINO1 1 Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan, 2Division of Cardioangiology, Nephrology and Endocrinology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan Background: The effect of cardiac resynchronization therapy (CRT) is controversial for long-term prognosis in patients with severe heart failure in the previous study. Objectives: To clarify long-term prognosis in patients treated with CRT. Methods: The subjects were 24 consecutive CRT patients admitted to our institute from 2006 to 2014 (21 males and 3 females). We retrospectively evaluated patient characteristics and electrocardiogram just before and after CRT implanted. Cardiac events were defined as heart failure requiring hospitalization/death from cardiovascular events. Results: Average age at CRT implantation was 60614 years in the study patients. Basal heart disease were as follows: dilated cardiomyopathy 15, ischemic heart disease 3, and the others 6. Average BNP level before CRT implantation decreased to after CRT implantation (8206676 pg/ml to 5876771 pg/ml; p50.206). However, QRS widths just before and after CRT implantation were 150627 and 146622