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The Clinical Evaluation of Drugs in the Treatment of Acute Heart Failure: The Regulatory Perspective
The 18th Annual Scientific Meeting JHFS Europe and ADHERE and OPTIMIZE-HF in the USA. However, the management strategies of worsening HF may be different from countries according to healthcare system. Thus, more complete understanding of characteristics, in-hospital management, and outcomes of these patients in an observational database is definitely needed in Japan. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARECARD) studied prospectively the characteristics and management in a broad sample of patients hospitalized with worsening HF in Japan and the outcomes including death and rehospitalization were followed in a web-based registry. The characteristics, clinical status, and laboratory data on admission were similar between JCARE-CARD and registries from the USA and Europe. Management was also similar except for higher use of carperitide and angiotensin receptor blocker. The most striking difference was the longer length of stay in Japan. These findings would be useful for the development of optimal management strategy for Japanese patients hospitalized with worsening HF.
The Clinical Evaluation of Drugs in the Treatment of Acute Heart Failure: The Regulatory Perspective KAORI SHINAGAWA Pharmaceuticals and Medical Devices Agency Acute heart failure (AHF) is a growing public health problem, and very few treatments have been introduced in the last 10 years. Since it is difficult to conduct large-scale confirmatory trials for mortality in Japan, it is necessary to provide endpoints for HF trials in Japan. For this purpose, the guidelines on the clinical evaluation of drugs in the treatment of heart failure were issued in 2011. Requirements for a drug to receive approval of an indication for AHF are 1. improvements in short-term mortality and morbidity, and 2. at least maintain long-term mortality. Just improvement of hemodynamics is not sufficient, we also need a short-term mortality benefits or an improvement of clinical signs and symptoms related to hemodynamics. The evaluation of efficacy will depend on the pharmacological profile and mechanism of action of the drug and the expected therapeutic targets. On top of choosing the optimal primary endpoint, secondary endpoints should include endpoints related to symptoms and QOL. Issues for drug development for AHF include the wide variety of disease backgrounds, and the difficulty to reach consensus onhow to measure and evaluate subjective endpoints. Moving forward, standardization and validation of end-points measures is critical. Future collaborative effortsbetween academia, industry, and regulatory agencies will be required in order to evaluate new therapies in the most efficient way possible. Heterogenous Nature of Acute Heart Failure Syndrome and the Necessity of a Standardized Grading System for Its Clinical Presentation KAZUHIKO HASHIMURA CardioVascular Center, Hanwa Memorial Hospital, Osaka, Japan ACE inhibitors/ARBs, beta blockers, mineral corticoid receptor antagonists and digoxin have shown effectiveness in HFrEF, but not in HFpEF. Both of HFrEF and HFpEF are considered a “syndrome”, due to its heterogenous nature; (1) pathophysiology (arterial underfilling, volume accumulation, central volume shift and abnormal blood pressure control by carotid baroreceptor etc.), (2) comorbid disease (hypertension, CKD, DM, lipid disorder, etc.), (3) left ventricular geometry (normal, dilated, concentric hypertrophy, concentric remodeling, eccentric hypertrophy) and (4) clinical presentation (rapid or gradual onset, pulmonary or systemic congestion, body weight gain + or -, etc.). This heterogeneity may have resulted in lack of significant results in previous heart failure syndrome-related large-scale clinical trials. A more narrowed inclusion criterion is therefore essential in future studies. In addition to the heterogeneity of heart failure syndrome, the absence of a standardized criterion to evaluate the degree of pulmonary/systemic congestion, and peripheral perfusion may have also complicated result interpretation in these trials. Due to this absence, a thorough clinical assessment analyzing the degree of congestion is not routinely performed during hospitalization and before discharge. Future practice should involve; 1) a subjective and objective grading system assessing volume status with dynamic postural change and 2) utilization of diagnostic devices capable of detecting asymptomatic congestion.
Symposium 6 Evidence of the Biomarkers from the Sub-analysis Data of Clinical Trials and Registries YUKIHITO SATO Division of Cardiovascular Medicine, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan Biomarkers are substances derived from organs, which can be measured and evaluated as indicators of normal biology, pathogenic process or pharmacological response to a therapeutic intervention. Their measurements is not subject to inter-observer variability. An ideal biochemical marker should be a prognostic indicator, assist in the early diagnosis of heart failure (HF), reliably reflect the therapeutic response, and help grading the risk associated with each stage of HF. While several biochemical markers have been studied for their prognostic value in the setting of chronic and acute HF, their clinical applications have not been systematically discussed. Moreover, change of ideal biomarkers should correlate the change of cardiovascular events. The relationship between cardiac remodeling and these biomarkers also should be elucidated. Finally, an ideal biochemical marker should be applicable to patients at the risk stage of HF. Biomarkers, such as CRP, BNP, collagen marker and high sensitive cardiac troponin has been reported as a prognostic marker of cardiovascular events in general population.
S137
In this symposium, we review biomarkers from the sub-analysis data of clinical trials and registries from, risk stage to overt HF.
Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) HIROYUKI TSUTSUI Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan Heart failure (HF) is a leading cause of mortality and hospitalization for adults older than 65 years in the industrialized countries. The characteristics and outcomes of HF patients have been described by several epidemiological studies and large scale clinical trials, performed mainly in the United States and Europe, whereas very little information is available in Japan. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARECARD) prospectively studied the characteristics, treatment, and outcomes of a broad sample of patients hospitalized with worsening HF at teaching hospitals throughout Japan. Demographics, medical history, severity, treatment, and outcome data were collected and entered into a database via secure web browser technology. It enrolled 2,675 patients at 164 participating hospitals with an average follow-up of 2.2 years. It provided various important insights into the “real-world” characteristics, the prognostic predictors, and the improved management strategies of HF patients in routine clinical practice in Japan. The Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) Study YAUSHIKO SAKATA, KOTARO NOCHIOKA, MASANOBU MIURA, SOICHIRO TADAKI, RYOICHI USHIGOME, TAKESHI YAMAUCHI, JUN TAKAHASHI, SATOSHI MIYATA, HIROAKI SHIMOKAWA Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan The Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study is one of the largest prospective observational multicenter cohort studies in Japan, designed to identify the characteristics, mortality and prognostic risks of patients with chronic heart failure (HF) and patients with cardiovascular disease (CVD) who are at high risk for development of de-novo HF. Between October 2006 and March 2010, a total of 10,219 patients with overt HF (Stage C/D), structural cardiac disorder but without HF (Stage B), or with coronary artery disease (Stage A) were successfully enrolled, and are currently being followed-up. The mean patient age was 68.2 12.3 years and male patients accounted for 69.8%. Overt HF was observed in 46.3% of patients (Stage C/D), and 53.7% did not have HF but were at high risk for transition to de-novo HF (Stage A/B). Compared with our previous CHART-1 study, the prevalence of ischemic etiology and cardiovascular risk factors, such as hypertension and diabetes, has increased, and prognosis has been improved along with implementation of evidence-based medications. Importantly, the trend of westernization of ischemic etiology was characterized mostly by an increase of patients with ischemic heart failure with preserved left ventricular ejection fraction. In this session, recent trends in the management and outcomes of CHF patients in the CHART studies will be presented.
Symposium 8 Current Perspectives on Cardiac Regenerative Therapy with Human Induced Pluripotent Stem Cells JUN FUJITA Department of Cardiology, Keio University School of Medicine, Tokyo, Japan Heart failure (HF) is the leading cause of death in developed countries. Heart transplantation is the only radical treatment of severe HF; however, donor shortage remains an unsolved problem. Induced pluripotent stem cell (iPSC) generation is a revolutionary technology as an infinite cell source for cardiomyocytes (CM). Therefore regenerative medicine with iPSCs has promised to fulfill this unmet medical need. However, clinical application of iPSCs needs to be achieved step by step. The establishment of safe iPSCs in xeno-free condition must be a first step, while genome integration-free and oncogene-free reprogramming is necessary. Cell culture systems for massive amount of both undifferentiated iPSCs and differentiated CM are also essential, because an adult heart contains more than 1x109 CM. Tumorigenicity is another potential of undifferentiated iPSCs. It will be a great tragedy, if it happens in a patient’s heart. Thus, the differentiated CM from iPSCs must be purified to exclude any possibility of tumorigenicity. The transplantation strategies used for iPSC-derived CM are very important for the recovery of lost cardiac function. Preclinical studies with large animal models, such as pigs, must be performed to verify the safety and efficacy of iPSCs-derived CM transplantation. Feasible and carefully optimized techniques for each stage must inevitably be established to realize regenerative therapy for advanced HF using iPSC-derived CM.
A New Evaluation Method for Reverse Remodeling Viability of Heart Failure MACHIKO KANZAKI, YOSHIHIRO ASANO, YASUSHI SAKATA Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Numerous studies tried to solve the pathophysiology of heart failure, but we can hardly know the point of no return in developing heart failure. If we can succeed in predicting the future prognosis of heart failure in the early stage, the earlier
The Clinical Evaluation of Drugs in the Treatment of Acute Heart Failure: The Regulatory Perspective KAORI SHINAGAWA Pharmaceuticals and Medical Devices Agency Acute heart failure (AHF) is a growing public health problem, and very few treatments have been introduced in the last 10 years. Since it is difficult to conduct large-scale confirmatory trials for mortality in Japan, it is necessary to provide endpoints for HF trials in Japan. For this purpose, the guidelines on the clinical evaluation of drugs in the treatment of heart failure were issued in 2011. Requirements for a drug to receive approval of an indication for AHF are 1. improvements in short-term mortality and morbidity, and 2. at least maintain long-term mortality. Just improvement of hemodynamics is not sufficient, we also need a short-term mortality benefits or an improvement of clinical signs and symptoms related to hemodynamics. The evaluation of efficacy will depend on the pharmacological profile and mechanism of action of the drug and the expected therapeutic targets. On top of choosing the optimal primary endpoint, secondary endpoints should include endpoints related to symptoms and QOL. Issues for drug development for AHF include the wide variety of disease backgrounds, and the difficulty to reach consensus onhow to measure and evaluate subjective endpoints. Moving forward, standardization and validation of end-points measures is critical. Future collaborative effortsbetween academia, industry, and regulatory agencies will be required in order to evaluate new therapies in the most efficient way possible. Heterogenous Nature of Acute Heart Failure Syndrome and the Necessity of a Standardized Grading System for Its Clinical Presentation KAZUHIKO HASHIMURA CardioVascular Center, Hanwa Memorial Hospital, Osaka, Japan ACE inhibitors/ARBs, beta blockers, mineral corticoid receptor antagonists and digoxin have shown effectiveness in HFrEF, but not in HFpEF. Both of HFrEF and HFpEF are considered a “syndrome”, due to its heterogenous nature; (1) pathophysiology (arterial underfilling, volume accumulation, central volume shift and abnormal blood pressure control by carotid baroreceptor etc.), (2) comorbid disease (hypertension, CKD, DM, lipid disorder, etc.), (3) left ventricular geometry (normal, dilated, concentric hypertrophy, concentric remodeling, eccentric hypertrophy) and (4) clinical presentation (rapid or gradual onset, pulmonary or systemic congestion, body weight gain + or -, etc.). This heterogeneity may have resulted in lack of significant results in previous heart failure syndrome-related large-scale clinical trials. A more narrowed inclusion criterion is therefore essential in future studies. In addition to the heterogeneity of heart failure syndrome, the absence of a standardized criterion to evaluate the degree of pulmonary/systemic congestion, and peripheral perfusion may have also complicated result interpretation in these trials. Due to this absence, a thorough clinical assessment analyzing the degree of congestion is not routinely performed during hospitalization and before discharge. Future practice should involve; 1) a subjective and objective grading system assessing volume status with dynamic postural change and 2) utilization of diagnostic devices capable of detecting asymptomatic congestion.
Symposium 6 Evidence of the Biomarkers from the Sub-analysis Data of Clinical Trials and Registries YUKIHITO SATO Division of Cardiovascular Medicine, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan Biomarkers are substances derived from organs, which can be measured and evaluated as indicators of normal biology, pathogenic process or pharmacological response to a therapeutic intervention. Their measurements is not subject to inter-observer variability. An ideal biochemical marker should be a prognostic indicator, assist in the early diagnosis of heart failure (HF), reliably reflect the therapeutic response, and help grading the risk associated with each stage of HF. While several biochemical markers have been studied for their prognostic value in the setting of chronic and acute HF, their clinical applications have not been systematically discussed. Moreover, change of ideal biomarkers should correlate the change of cardiovascular events. The relationship between cardiac remodeling and these biomarkers also should be elucidated. Finally, an ideal biochemical marker should be applicable to patients at the risk stage of HF. Biomarkers, such as CRP, BNP, collagen marker and high sensitive cardiac troponin has been reported as a prognostic marker of cardiovascular events in general population.
S137
In this symposium, we review biomarkers from the sub-analysis data of clinical trials and registries from, risk stage to overt HF.
Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) HIROYUKI TSUTSUI Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan Heart failure (HF) is a leading cause of mortality and hospitalization for adults older than 65 years in the industrialized countries. The characteristics and outcomes of HF patients have been described by several epidemiological studies and large scale clinical trials, performed mainly in the United States and Europe, whereas very little information is available in Japan. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARECARD) prospectively studied the characteristics, treatment, and outcomes of a broad sample of patients hospitalized with worsening HF at teaching hospitals throughout Japan. Demographics, medical history, severity, treatment, and outcome data were collected and entered into a database via secure web browser technology. It enrolled 2,675 patients at 164 participating hospitals with an average follow-up of 2.2 years. It provided various important insights into the “real-world” characteristics, the prognostic predictors, and the improved management strategies of HF patients in routine clinical practice in Japan. The Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) Study YAUSHIKO SAKATA, KOTARO NOCHIOKA, MASANOBU MIURA, SOICHIRO TADAKI, RYOICHI USHIGOME, TAKESHI YAMAUCHI, JUN TAKAHASHI, SATOSHI MIYATA, HIROAKI SHIMOKAWA Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan The Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study is one of the largest prospective observational multicenter cohort studies in Japan, designed to identify the characteristics, mortality and prognostic risks of patients with chronic heart failure (HF) and patients with cardiovascular disease (CVD) who are at high risk for development of de-novo HF. Between October 2006 and March 2010, a total of 10,219 patients with overt HF (Stage C/D), structural cardiac disorder but without HF (Stage B), or with coronary artery disease (Stage A) were successfully enrolled, and are currently being followed-up. The mean patient age was 68.2 12.3 years and male patients accounted for 69.8%. Overt HF was observed in 46.3% of patients (Stage C/D), and 53.7% did not have HF but were at high risk for transition to de-novo HF (Stage A/B). Compared with our previous CHART-1 study, the prevalence of ischemic etiology and cardiovascular risk factors, such as hypertension and diabetes, has increased, and prognosis has been improved along with implementation of evidence-based medications. Importantly, the trend of westernization of ischemic etiology was characterized mostly by an increase of patients with ischemic heart failure with preserved left ventricular ejection fraction. In this session, recent trends in the management and outcomes of CHF patients in the CHART studies will be presented.
Symposium 8 Current Perspectives on Cardiac Regenerative Therapy with Human Induced Pluripotent Stem Cells JUN FUJITA Department of Cardiology, Keio University School of Medicine, Tokyo, Japan Heart failure (HF) is the leading cause of death in developed countries. Heart transplantation is the only radical treatment of severe HF; however, donor shortage remains an unsolved problem. Induced pluripotent stem cell (iPSC) generation is a revolutionary technology as an infinite cell source for cardiomyocytes (CM). Therefore regenerative medicine with iPSCs has promised to fulfill this unmet medical need. However, clinical application of iPSCs needs to be achieved step by step. The establishment of safe iPSCs in xeno-free condition must be a first step, while genome integration-free and oncogene-free reprogramming is necessary. Cell culture systems for massive amount of both undifferentiated iPSCs and differentiated CM are also essential, because an adult heart contains more than 1x109 CM. Tumorigenicity is another potential of undifferentiated iPSCs. It will be a great tragedy, if it happens in a patient’s heart. Thus, the differentiated CM from iPSCs must be purified to exclude any possibility of tumorigenicity. The transplantation strategies used for iPSC-derived CM are very important for the recovery of lost cardiac function. Preclinical studies with large animal models, such as pigs, must be performed to verify the safety and efficacy of iPSCs-derived CM transplantation. Feasible and carefully optimized techniques for each stage must inevitably be established to realize regenerative therapy for advanced HF using iPSC-derived CM.
A New Evaluation Method for Reverse Remodeling Viability of Heart Failure MACHIKO KANZAKI, YOSHIHIRO ASANO, YASUSHI SAKATA Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Numerous studies tried to solve the pathophysiology of heart failure, but we can hardly know the point of no return in developing heart failure. If we can succeed in predicting the future prognosis of heart failure in the early stage, the earlier