Points of View Cardiovascular Disease

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Minoru Ito, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

1. Introduction

One of the key goals of next-generation health care is to "extend healthy life expectancy. To realize this goal, the focus of health care should shift from "diagnosis and treatment," which focuses on curing diseases, to "prevention" and "symbiosis," in which people can live their lives with as few restrictions as possible even if they suffer from diseases. When considering "extension of healthy life expectancy," cardiovascular diseases have a significant impact on healthy life expectancy, as described below. It is no exaggeration to say that countermeasures against cardiovascular diseases are a national issue, as they also have a significant impact on the causes of death and national health care costs in Japan. Therefore, the purpose of this report is to understand the status of cardiovascular diseases and how they should be addressed, as well as the development status of therapeutic drugs to which the pharmaceutical industry can contribute, and the status of related medical DX. It is well known that drugs for hypertension, hyperlipidemia, etc. have made important contributions to the reduction of cardiovascular diseases, but the scope of this report does not cover such prophylactic drugs.

What is cardiovascular disease?

Cardiovascular disease is a combination of stroke and heart ^disease1) and includes ischemic stroke (cerebral infarction), hemorrhagic stroke (intracerebral hemorrhage, subarachnoid hemorrhage, etc.), transient ischemic attack, ischemic heart disease (angina pectoris, myocardial infarction, etc.), heart failure, arrhythmia, valvular disease (aortic stenosis, mitral regurgitation, etc.), aortic ²⁾ In this report, we focus on cerebrovascular diseases (stroke: cerebral infarction, intracerebral hemorrhage, subarachnoid hemorrhage, etc.) and ischemic heart diseases (angina pectoris, myocardial infarction, etc.), which are relatively common in the number of patients. and myocardial infarction, etc.), which account for a relatively large number of patients.

^The term "lifestyle-related diseases" is a general term for diseases that are closely related to lifestyle habits such as diet, exercise, rest, smoking, and alcohol consumption, and which are factors in their pathogenesis. (3) The World Health Organization (WHO) uses the term NCDs (non-communicable diseases) as a similar concept, which includes diabetes and COPD in addition to cardiovascular diseases and cancer.

Cardiovascular disease has a significant impact on the health of the population: in the 2018 Vital Statistics, heart disease was the second leading cause of death and cerebrovascular disease was the fourth leading cause of death; together, they are the second leading cause of death after "cancer," killing over 310,000 people annually. Furthermore, according to the 2017 edition of the "National Medical Expenditure" overview, of the 30,833.5 billion yen in medical care expenditures by injury and disease category in the same year, diseases of the circulatory system accounted for the largest share, at 6,078.2 billion yen (19.7%).

In addition, according to the 2019 National Survey of Population, cerebrovascular diseases and cardiac diseases accounted for 16.1% and 4.5%, respectively, of the major causes of the need for long-term care, and together they accounted for the largest percentage of 20.6%. In relation to this issue, the author examined the percentage transition from 2001 to 2019 by age structure in Policy Research Institute News No. 65 (March 2022) ⁴⁾. In particular, cerebrovascular disease (stroke) accounts for about 60% of the causes of death among those insured under the second category of long-term care insurance (aged 40-64), and the number is slowly increasing each year, posing a major threat to the health of the mature age group.

In the clinical course of cardiovascular disease, stroke and cardiovascular disease have both common and different characteristics. One common feature is the rapid onset of stroke, which can be life-threatening and lead to sudden death within minutes to hours in the acute phase. Even if death does not occur, strokes, in particular, often leave severe sequelae. However, prompt treatment after the onset of stroke may improve prognosis, including sequelae. In the recovery and maintenance phases (chronic phase), patients are always at risk of developing severe symptoms or sudden deterioration, and are prone to recurrence or exacerbation. On the other hand, there are differences in the course of the acute, convalescent, and maintenance phases. Compared to cardiovascular diseases, strokes often require long-term hospitalization during the recovery phase, and rehabilitation aimed at restoring physical functions is necessary before patients can return to society. However, the convalescent management of cardiovascular disease is often performed in an outpatient setting once the condition has stabilized ^.5) (Figure 1)

Estimated Number of Patients with Cardiovascular Disease

Figure 2 shows the estimated number of patients with cardiovascular disease based on a patient ^survey6) conducted by the Ministry of Health, Labour and Welfare. The survey is conducted every three years, and the latest results (2020 patient survey) were released in June 2022. As a result, the total estimated number of cerebrovascular disease patients (inpatients + outpatients) was 389.8 (thousand) in 1996, but has decreased almost consistently to 197.5 (thousand) in 2020. However, as mentioned above, the current situation still has a significant impact on the health of the population.

The total population of Japan peaked at 127.84 million in 2004 and has been declining since then. Therefore, in order to adjust for the impact of population decline, the estimated patient rate was calculated by dividing the estimated number of patients by the estimated ^{population7) of the} same year, and the changes are shown in Figure 3. The result shows almost the same behavior as that of the estimated number of patients, with the estimated patient rate, which was 0.31% in 1996, decreasing almost consistently to 0.16% in 2020. The above suggests that there is no doubt that the number of patients with cardiovascular disease is on a downward trend.

The incidence of cardiovascular disease is related to multiple factors, including diet (including low-sodium diet), exercise, smoking, hypertension, and hypercholesterolemia, and the incidence rate decreases according to the degree of improvement of these ^factors8). The status of these factors may be involved in the decline in the number of patients with cardiovascular disease, but because of the multifactorial nature of the disease, the degree of involvement of individual factors is not clear.

Countermeasures for Cardiovascular Disease

4-1 Basic Act on Measures against Stroke and Cardiovascular Diseases

An important event in considering cardiovascular disease countermeasures in recent years was the promulgation in December 2018 of the Basic Act on Measures Concerning Stroke, Heart Disease, and Other Cardiovascular Diseases to Extend Healthy Life Expectancy, etc. (Basic Act on Stroke and Cardiovascular Disease Countermeasures) (hereinafter, Basic Act). The ^schedule9) of cardiovascular disease countermeasures starting with the Basic Law is shown in Figure 4. The Basic Law stated as its "objective" the "comprehensive and systematic promotion of cardiovascular disease countermeasures," and as its "basic principles" (1) public awareness, (2) development of health, medical, and welfare service delivery systems, and (3) promotion of research, provision of information, and development and provision of products and services The Basic Law went into effect on December 1, 2019. Immediately after, in January 2020, the Council on Cardiovascular Disease Control was organized and the Basic Plan for the Promotion of Cardiovascular Disease Control ("Basic Plan") was formulated based on the Basic Law and published in October 2020. This clarified the basic direction of the country's cardiovascular disease countermeasures. In addition, based on the Basic Plan, a Cardiovascular Disease Countermeasures Promotion Plan was prepared by prefectures, and a system to promote countermeasures in cooperation among the national government, local governments, and medical insurers was established. ²⁾

4-2 Basic Plan to Promote Measures against Cardiovascular Diseases

An overview of the basic plan is shown in Figure 510 ⁾. The overall goal of the basic plan is to "extend healthy life expectancy by at least three years and reduce age-adjusted mortality from cardiovascular diseases by 2040" by achieving three goals: (1) prevention of cardiovascular diseases and promotion of correct knowledge, (2) improvement of health, medical care, and welfare service delivery systems, and (3) promotion of research on cardiovascular diseases. (2) Improvement of health, medical care, and welfare service delivery systems, and (3) Promotion of cardiovascular disease research. In addition, since multiple factors are involved in the onset and severity of cardiovascular disease, it was decided to establish a system for collecting and providing a wide range of medical information as the basis for overall countermeasures, and to aim for clarification of the actual conditions of the disease.

The basic plan must be reviewed at least every six years and revised when necessary. The implementation period of the first phase of the basic plan is set at about three years, from FY2020 to FY2022. Currently (September 2022), the direction of the second basic plan is being considered. Although it is still in the draft stage, the basic ideas include updating evaluation indicators related to cardiovascular diseases, coordination with the 8th Medical Plan and the 9th Long-Term Care Insurance Business Plan scheduled to start in FY2024, and the development of a medical system that can maintain functionality even during the spread of COVID-19 infection. ⁹⁾

4-3. Research Projects for Cardiovascular Disease

AMED is promoting the Practical Application Research Project for Countermeasures against Cardiovascular Diseases and Lifestyle Related Diseases such as Diabetes ^Mellitus11). The project's goal is to promote research on lifestyle-related diseases in two areas: "health promotion and prevention of the onset of lifestyle-related diseases" and "lifestyle-related disease management. Specifically, the project aims to develop devices and software that promote behavioral change for the prevention of lifestyle-related diseases; conduct research and development that contributes to the prevention of severe lifestyle-related diseases and improvement of prognosis and QOL after severe disease, etc., optimized for individuals; establish new health promotion methods to prevent the onset of lifestyle-related diseases using AI, etc.; and promote the elucidation of the pathogenesis of cardiovascular diseases and the development of innovative The government also stated that it would promote research and development that contributes to the elucidation of the pathogenesis of cardiovascular diseases and to innovative prevention, diagnosis, treatment, and rehabilitation (Figure 6). (Figure 6)

The Ministry of Health, Labour and Welfare (MHLW) is promoting the Comprehensive Research Project for Measures against Cardiovascular Diseases, Diabetes and Other Lifestyle Related ^Diseases13). The project goal is to promote epidemiological research, clinical research, and research bridging to clinical practice on representative lifestyle-related diseases other than cancer, with the aim of generating evidence that will contribute to the field of health and medical care and to administrative measures. The following three research scopes are proposed. (1) In the "health promotion field," the project aims to evaluate policies that contribute to extending healthy life expectancy and reducing health disparities by improving individual lifestyles and the social environment, and to create evidence to support such policies. (2) In the "health checkup and health guidance field," the project aims to implement effective and efficient health checkups and health guidance (improvement of quality, examination of provision systems, effective use of results, etc.). (3) In the field of "lifestyle-related disease management," the aim is to elucidate the pathophysiology of lifestyle-related diseases, propose policies to solve such diseases, equalize treatment, and maintain and improve the quality of life of people with lifestyle-related diseases (Figure 7). (Figure 7)

In the basic plan, it is pointed out that multiple factors are involved in the onset and severity of cardiovascular disease, that the pathogenesis of the disease is not fully clarified, and that most treatment methods are limited to symptomatic treatment. ²⁾ Early research results are also expected to improve the quality of medical care and extend healthy life expectancy.

4-4. measures for cardiovascular disease in the U.S.

As a reference for Japanese countermeasures, we surveyed U.S. countermeasures. Healthy People 2030 ("HP2030") ¹⁵⁾ plays a major role in the U.S. measures against cardiovascular diseases. It is an initiative launched in 1979 by the United States Department of Health and Human Services (HHS), a national agenda that provides health improvement priorities, objectives, and targets (from 2020 to 2030). HP2030 targets several diseases and health conditions, one of which is Heart Disease and Stroke (Heart Disease and Stroke).

In the U.S., age-adjusted mortality from cardiovascular disease is declining, but heart disease is the leading cause of death, and stroke is the fifth leading cause of death, making cardiovascular disease a major contributor to the nation's health. ¹⁶⁾ This situation is similar to Japan. HP2030 focuses on the prevention and treatment of cardiovascular disease and the improvement of related overall health. The HP2030 focuses on the prevention and treatment of cardiovascular disease and the improvement of overall health: strengthening control of hypertension and cholesterol as preventive care (statins are recommended for people at high risk of heart disease), promoting healthy diet and exercise to contribute to this, providing timely treatment at the onset (fibrinolysis and percutaneous coronary angioplasty for heart attack patients, and intravenous revascularization and thrombectomy for stroke patients), and providing treatment for stroke patients at the time of onset. ), and rehabilitation and aspirin therapy to avoid recurrence or exacerbation of disease after onset. ⁽¹⁵⁾ It was inferred that these measures have much in common with those taken in Japan. On the other hand, the fact that the goals of emergency response are clearly stated as increasing the rate of cardiopulmonary resuscitation and AED (automated external defibrillator) use in non-traumatic cardiac arrest may be helpful for Japan in terms of strengthening response in the early stages of cardiovascular disease onset and raising public knowledge about the necessity of such measures.

Development of therapeutic drugs (contribution of the pharmaceutical industry)

When considering the contribution of the pharmaceutical industry to cardiovascular disease, the development of therapeutic drugs is expected to be the most significant. The survey was conducted on global trends in therapeutic drug development. The survey was conducted using the global search function of "Tomorrow's New Drugs (Technomic Co., Ltd.). The fields were pharmaceuticals and regenerative medicine, and the stages were categorized as active: preclinical, clinical preparation, Phase 1-3, in preparation for filing, filed, approved, and already on the market. The "discontinued/no follow-up report" was excluded, and "approved/launched" was limited to items approved or launched in 2016 or later, since older items were also included. The indications for cerebral diseases were searched as "cerebrovascular disease, subarachnoid hemorrhage, cerebral thrombosis, cerebral infarction, cerebral arteriosclerosis, cerebral hemorrhage, cerebral ischemia, cerebral embolism, stroke, ischemic stroke, acute cerebral embolism" and for cardiac diseases as "ischemic heart disease, angina pectoris, myocardial infarction, coronary atherosclerosis, heart failure, cardiomyopathy, arrhythmia, heart disease".

As a result, the number of global development items (meaning the number of all hit items in the global search) in cardiovascular diseases (brain diseases and heart diseases) as of September 10, 2022 was calculated. The number of products under development for multiple indications was 37 for brain diseases and 63 for cardiac diseases. By country, the top three brain disease drugs were 31 from the U.S., 12 from Japan, and 8 from Europe, while the top three cardiac disease drugs were 44 from the U.S., 25 from Japan, and 17 from Europe, in that order. In terms of breakdown by field, the 37 global brain disease products consisted of 32 pharmaceuticals and 5 cell therapy products. The development of cell therapy, a new modality, was active in both Japan and the U.S., with four products in each country. The 63 cardiac disease products consisted of 47 drugs, 9 cell therapy products, and 7 gene therapy products, with active development of cell therapy products in Japan (7 products) and gene therapy products in the U.S. (6 products). (Table 1)

We continued our review of the current development status. Table 2 shows the development status of brain diseases and Table 3 shows the development status of cardiac diseases. In cases where the same product is being developed for multiple indications, the development progress differs depending on the indication, so the data were tabulated separately for each indication. As a result, many of the products were in phase 2 or 3 of development. However, in the U.S., the number of products in younger phases such as preclinical and phase 1 tended to be relatively high, indicating that new development is active.

Furthermore, we examined what indications of cardiovascular disease the products are being developed for. Table 4 shows the indications for which products are being developed. When the same product is being developed for multiple indications, the global situation is shown by tabulating each indication separately, and the Japanese situation is shown as an inner number. As a result, in the area of brain diseases, stroke was by far the most common indication, followed by cerebral infarction, although cerebral infarction was more common in Japan. Among cardiac diseases, heart failure was the most common, followed by cardiomyopathy and myocardial infarction. The situation in Japan was similar.

The development of therapeutic drugs showed that the pharmaceutical industry is making a reasonable contribution to cardiovascular diseases. A relatively large number of products are in Phase II and III development for both brain and cardiac diseases, and new modalities such as cell therapy and gene therapy were also seen in some cases. It is hoped that the early launch of these developments and guaranteed access to them by the public will contribute to the fight against cardiovascular disease.

Medical DX related to cardiovascular disease 7.

As mentioned earlier, the progression of cardiovascular disease may be controlled by improving lifestyle, and lifestyle improvement is important not only for preventing the onset of the disease, but also for preventing its recurrence and severity. In his research paper, "Advances in Digital Technology and Paradigm Shift in Medical Health Care," Sasaki described the first half of the 21st century as the "century of behavior change," pointing out that advances in digital technology are behind the development of behavior change approaches. ¹⁷⁾ The Basic Plan for the Promotion of Measures against Cardiovascular Diseases includes the following three elements (17) The Basic Plan for the Promotion of Measures against Cardiovascular Diseases states that the development of innovative diagnostic and therapeutic methods through the use of digital technology, such as the use of large-scale data and image diagnosis by AI, is required, and it was considered necessary to pay attention to the progress of medical DX.

In the course of the study, we investigated events that may be related to cardiovascular diseases. Unfortunately, there are no databases or other tools available to fully investigate medical DX, so we collected and categorized information related to medical DX for the past two years from various ^media18), both domestic and foreign. The classification was based on the two axes of "diseases" and "interventions. Diseases were categorized into "brain" and "heart," and information common to both was labeled as "cardiovascular. Interventions were divided into four categories: "prevention," "diagnosis," "treatment," and "prognosis care. Results are shown in Table 5. On the disease axis, "cardiac" was the most common, and on the intervention axis, information related to "diagnosis" was the most common.

Typical information is exemplified below.

As for information other than news search, the "Research and Study Project on Prevention of Serious Illness by Health Management System Utilizing AI" was adopted by the Ministry of Health, Labour and Welfare's Health Promotion Project for the Elderly under the Subsidy for Promotion of Health Service for the Elderly in FY2048, and a report was presented in March 2020. This study examined the possibility of a model to improve the quality and efficiency of home medical care and nursing care by collecting vital data of home patients and users and using AI to detect abnormalities. The surveyed collaborators had a history of "stroke" and "heart disease. As a result, it was summarized that a certain level of feasibility and usefulness were confirmed. ²³⁾

Medical DX initiatives related to cardiovascular disease are advancing in a wide range of phases, not only in diagnosis and treatment, but also in prevention and prognostic care, and are spreading not only to the medical field but also to the nursing care field. The trends of these new initiatives will require continued attention.

7. summary

Although the number of patients with cardiovascular diseases is on the decline, they still occupy a major position in terms of mortality, the main causes of the need for nursing care, and medical costs, and are diseases that have a significant impact on the lives and healthy life expectancy of the population and society as a whole. after the enactment of the basic law in 2018, the cooperation of the national government, local governments, and others is progressing and the battle lines are being set up. The fight against the disease has only just begun. The pharmaceutical industry is expected to contribute most to the development of therapeutic drugs, including efforts to address new modalities. The Basic Plan points out that many factors are involved in the onset and severity of cardiovascular disease, the pathophysiology of the disease is not fully understood, and most treatment remains ^{symptomatic2)}. 2). It can be said that basic research, mainly in academia, should continue to be focused on elucidating pathological conditions. In addition, the efforts of medical DX have the potential to cover a wide range of areas, including prevention, diagnosis, treatment, and prognostic care, and we look forward to future developments in this area. Since lifestyle improvement is important for cardiovascular disease, it is desirable for the public to actively participate in the fight against the disease by changing their behavior. In this sense, measures to combat cardiovascular disease should be positioned as a concerted effort by the entire nation. 2.

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