Cardiovascular disease risk assessment and multidisciplinary care in prostate cancer treatment with ADT: recommendations from the APMA PCCV expert network.

PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.

Long-term effects of lowering postprandial glucose level on cardiovascular outcomes in early-stage diabetic patients with coronary artery disease: 10-year post-trial follow-up analysis of the DIANA study.

AIMS: To elucidate the long-term cardiovascular benefit of lowering postprandial hyperglycemia (PPG) in early-stage T2DM patients. METHODS: This 10-year post-trial follow-up study included 243 patients from the DIANA (DIAbetes and diffuse coronary Narrowing) study, a multi-center randomized controlled trial which compared the efficacy of one-year life-style and pharmacological (voglibose/nateglinide) intervention lowering PPG on coronary atherosclerosis in 302 early-stage T2DM subjects [impaired glucose tolerance (IGT) or newly-diagnosed T2DM] (UMIN-CTRID#0000107). MACE (all-cause death, non-fatal MI or unplanned coronary revascularization) were compared in (1) three assigned therapies (life-style intervention/vogliose/nateglinide) and (2) patients with and without improvement of PPG (reversion from IGT to NGT or from DM to IGT/NGT on 75 g oral glucose tolerance test). RESULTS: During the 10-year post-trial observational period, voglibose (HR = 1.07, 95%CI: 0.69-1.66, p = 0.74) or nateglinide (HR = 0.99, 95%CI: 0.64-1.55, p = 0.99) did not reduce MACE. Similarly, achieving the improvement of PPG was not associated with a reduction of MACE (HR = 0.78, 95%CI: 0.51-1.18, p = 0.25). However, in IGT subjects (n = 143), this glycemic management significantly reduced the occurrence of MACE (HR = 0.44, 95%CI: 0.23-0.86, p = 0.01), especially unplanned coronary revascularization (HR = 0.46, 95%CI: 0.22-0.94, p = 0.03). CONCLUSIONS: The early improvement of PPG significantly reduced MACE and unplanned coronary revascularization in IGT subjects during the post-trial 10-year period.

Prospective screening for myocarditis in cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) improve clinical outcomes in various cancers, but sometimes induce autoimmune adverse effects, including myocarditis, which is the most serious complication. There are many reports on ICI-induced myocarditis; however, only a few prospective surveillance reports exist. Therefore, we developed a prospective screening protocol and performed monitoring clinically suspected myocarditis in every patient treated with ICIs. METHODS: We prospectively enrolled 126 consecutive patients treated with ICIs in this cohort. Outcomes of patients were determined and analyzed between April 2017 and May 2020. We evaluated vital signs, biomarkers, electrocardiograms, chest radiographs, and echocardiographs before and at 7 ±â€¯3, 14 ±â€¯3, 21 ±â€¯3, and 60 ±â€¯7 days after ICI initiation. RESULTS: Eighteen (14.3 %) presented troponin I elevation and 13 of them presented signs of clinically suspected myocarditis (10.3 %). Among the 13 patients, ICI was discontinued in four cases (3.2 %) without fatal events. Myocarditis appeared at an early stage of ICI treatment, regardless of severity (median, 44 days). CONCLUSIONS: We observed the frequency of patients with myocarditis or myocardial damage through a prospective screening program in the real world. Although the frequency was higher than expected, most cases were mild and ICI treatment could be continued under careful observation.

Endovascular versus open repair in patients with abdominal aortic aneurysm: a claims-based data analysis in Japan.

Objectives: Endovascular aortic repair (EVAR) evolved through competition with open aortic repair (OAR) as a safe and effective treatment option for appropriately selected patients with abdominal aortic aneurysm (AAA). Although endoleaks are the most common reason for post-EVAR reintervention, compliance with lifelong regular follow-up imaging remains a challenge. Design: Retrospective data analysis. Setting: The Japan Medical Data Center (JMDC), a claims database with anonymous data linkage across hospitals, consists of corporate employees and their families of ≤75 years of age. Participants: The analysis included participants in the JMDC who underwent EVAR or OAR for intact (iAAA) or ruptured (rAAA) AAA. Patients with less than 6 months of records before the aortic repair were excluded. Main outcome measures: Overall survival and reintervention rates. Results: We identified 986 cases (837 iAAA and 149 rAAA) from JMDC with first aortic repairs between January 2015 and December 2020. The number of patients, median age (years (IQR)), follow-up (months) and post-procedure CT scan (times per year) were as follows: iAAA (OAR: n=593, 62.0 (57.0-67.0), 26.0, 1.6, EVAR: n=244, 65.0 (31.0-69.0), 17.0, 2.2), rAAA (OAR: n=110, 59.0 (53.0-59.0), 16.0, 2.1, EVAR: n=39, 62.0 (31.0-67.0), 18.0, 2.4). Reintervention rate was significantly higher among EVAR than OAR in rAAA (15.4% vs 8.2%, p=0.04). In iAAA, there were no group difference after 5 years (7.8% vs 11.0%, p=0.28), even though EVAR had initial advantage. There were no differences in mortality rate between EVAR and OAR for either rAAA or iAAA. Conclusions: Claims-based analysis in Japan showed no statistically significant difference in 5-year survival rates of the OAR and EVAR groups. However, the reintervention rate of EVAR in rAAA was significantly higher, suggesting the need for regular post-EVAR follow-up with imaging. Therefore, international collaborations for long-term outcome studies with real-world data are warranted.

Cardiotoxicity of adjuvant chemotherapy with trastuzumab: a Japanese claim-based data analysis.

OBJECTIVE: Adjuvant chemotherapy with trastuzumab improves the postoperative life expectancy of women with early-stage breast cancer. Although trastuzumab is reportedly cardiotoxic, quantification based on real-world evidence is lacking. Therefore, in this study, we aimed to analyse trastuzumab cardiotoxicity using a nationwide claim-based database. METHODS: In this retrospective study, we used data from a nationwide claims database (Japan Medical Data Center, Tokyo, Japan) under the universal healthcare system. Women with breast cancer who underwent initial surgery were included. Patients with recurrent or advanced-stage breast cancer, with a history of heart failure, receiving neoadjuvant chemotherapy or a preoperative history of less than 6 months were excluded. Propensity score (PS) was calculated using logistic regression based on age, cardiovascular risk factors, radiotherapy and concomitant anthracyclines (AC). RESULTS: We identified 12 060 eligible patients (mean age 50.8±8.56 years) between January 2010 and December 2019. After 1:2 PS matching (trastuzumab users, TZ, n=1005; non-users, NT, n=2010), Cox proportional hazards model analysis showed that the rate of heart failure development within 18 months postoperative was significantly higher in the TZ group than in the NT group (adjusted HR 2.28, 95% CI 1.38 to 3.77). Baseline cardiac evaluation in the combined AC/TZ cases was 27.2% preoperative, 66.0% pre-AC and 86.6% pre-TZ, respectively. CONCLUSION: Trastuzumab cardiotoxicity remained relevant in the claim-based analysis adjusted for AC effects. Further collaborative studies in cardio-oncology with real-world data are warranted to improve the rate of baseline cardiovascular risk assessment in patients with cancer scheduled for cardiotoxic cancer treatment.

Association between prenatal exposure to antidepressants and neonatal morbidity: An analysis of real-world data from a nationwide claims database in Japan.

BACKGROUND: Depression during pregnancy is relatively undertreated; however, the relationship between prenatal exposure to antidepressants and neonatal outcomes remains controversial. METHODS: This retrospective cohort study used a Japanese nationwide claims database. Data of 114,359 singletons born between January 2005 and November 2019 were used to evaluate the relationship between prenatal exposure to antidepressants and neonatal morbidity. RESULTS: Of 2892 mothers with a history of depression before delivery, 352 (12.1%) received prescriptions within three months before delivery (MP3), and 2540 did not (non-MP3). The participants were propensity score matched (PSM) in a ratio of 1:3 using logistic regression (MP3_PSM [n = 351] vs non-MP3_PSM [n = 1052]), and maternal prescriptions of antidepressants within three months before delivery were associated with neonatal morbidity indicators, including admission to the neonatal intensive care unit (NICU) (15.7 vs. 9.1%, odds ratio (OR) 1.9 [95% confidence interval (CI): 1.3-2.6]), poor neonatal adaptation syndrome (6.0 vs 1.0%, OR 6.6 [95% CI: 3.1-14.2]), transient tachycardia (15.7 vs. 6.7%, OR 2.6 [95% CI: 1.8-3.8]), and meconium aspiration syndrome (3.1 vs 0.7%, OR 4.8 [95% CI, 1.9-12.5]). There were no significant differences in the long-term duration of stay at the NICU (>15 days). LIMITATIONS: Confounding factors may remain even after the propensity matching. CONCLUSION: Maternal prescription of antidepressants within three months before delivery was associated with increased admission to the NICU. However, the absolute risk of severe neonatal morbidity was low. Therefore, collaborative care for prenatal depression and the neonatal intensive care is warranted.

Cardiovascular Complications Associated with Contemporary Lung Cancer Treatments.

OPINION STATEMENT: Lung cancer is the most common form of cancer in humans and the leading cause of cancer-related death worldwide. Traditionally, lung cancer has been diagnosed as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). However, recent developments in molecular pathology have revolutionized the diagnosis and treatment of the disease, thus improving patient prognosis and increasing the number of survivors. In advanced NSCLC cases, molecularly targeted drugs for patients with positive driver gene mutation/rearrangement, and immune checkpoint inhibitors for those with a positive biomarker, have changed the standard of care. SCLC is a highly malignant entity. In addition to the chemotherapy and radiotherapy, immune checkpoint inhibitors have recently provided some hope for extended-stage SCLC. Smoking cessation is related to decreased morbidity. However, early metastasis remains a significant challenge. Recently, cancer therapy-related cardiovascular disease (CTRCD) has emerged as diverse pathophysiology, including fulminant myocarditis, fatal arrhythmia, pericarditis, hypertension, and thrombosis, that emerged with modern lung cancer therapies. Cardio-oncology is a new interdisciplinary collaboration to develop methodologies to manage cardiovascular risk factors and CTRCDs with the common goal of minimizing unnecessary interruption of cancer treatment and maximizing outcomes of lung cancer survivors.

Guidelines for clinical evaluation of anti-cancer drugs.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.

Cardio-Oncology rehabilitation- challenges and opportunities to improve cardiovascular outcomes in cancer patients and survivors.

While the number of cancer patients is increasing with the arrival of the super-aging society, the age-adjusted mortality rate of cancer decreases due to medical advances, and the number of cancer survivors is growing rapidly. Cardiovascular disease (CVD) is one of the most important causes of death among cancer survivors. In recent years, the number of cancer patients with CVD risk factors has increased. Also, the emergence of new drugs has led to the emergence of a new condition called cancer treatment-related cardiovascular disease (CTRCD). Cardio-oncology (onco-cardiology) is a new multidisciplinary field with the common goal of completing cancer treatment and improving the prognosis of cancer patients and survivors, including the prevention, diagnosis, and treatment of CTRCD. Cardio-oncology rehabilitation (CORE) is a new concept that aims to reduce the risk of CVD and improve cardiopulmonary fitness in cancer survivors by providing exercise prescriptions and cardiac rehabilitation in addition to so-called cancer rehabilitation during and after cancer treatment. This review provides an overview of the theoretical background, feasibility, challenges, and opportunities of CORE, including a series of recent white papers and scientific statements released by the American Heart Association.

[Clinical pharmacology of cardio-oncology: a novel interdisciplinary platform for basic and translational research].

Advances in cancer treatment have led to dramatic increase in cancer survivors. In addition to cardiotoxicity resulting from anthracyclines and radiation therapy, the emergence of novel cancer treatment-related cardiovascular disease (CTRCD) with molecularly targeted therapies and immune checkpoint inhibitors has been recognized as an unmet medical need. Cardio-oncology is a new interdisciplinary research opportunity at the intersection of cardiovascular disease and cancer. Research priorities need to be identified for diagnosis, treatment, and prevention of previously unknown CTRCD(s), including (a) cardiac dysfunction and heart failure, (b) coronary artery disease, (c) valvular disease, (d) arrhythmias and QT-prolongation, (e) arterial hypertension, (f) thromboembolic disease, and (g) other cardiovascular disorders. In particular, understanding the fundamental mechanisms underlying CTRCD is essential for developing new methods. Applying more appropriate disease models and more effective methods for toxicity screening will help to better understand CTRCD. Although animal models have been used to predict potential problems, more advanced predictive models are also needed. Biobanks and other specimens with patient registries are expected to facilitate the validation of new biomarkers, genomic analysis, and imaging methods.

Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension.

We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.

Risk Profiling of Cancer Treatment-Related Cardiovascular Disorders in Breast Cancer Patients Who Received Adjuvant Chemotherapy With Trastuzumab.

Background: The prognosis of cancer survivors has dramatically improved, but effective strategies for cancer treatment-related cardiovascular disorders (CTRCD) remain to be elucidated in the emerging field of cardio-oncology. In this study, we investigated risk factors for CTRCD in breast cancer patients treated with trastuzumab. Methods and Results: We performed a retrospective analysis of 141 consecutive women who received adjuvant trastuzumab, and underwent baseline (BL) and follow-up (FU) echocardiography at Juntendo University between April 2010 and December 2016. The major concomitant treatment was anthracyclines in 94% and radiotherapy in 53%. During the median treatment period of 11 months, there were 22 (15.6%) cardiology consultations, 3 (2.1%) treatment interruptions with irreversible CTRCD, and no deaths. Left ventricular ejection fraction (LVEF) was decreased from a median 67.5% (BL) to 63.4% (FU; P<0.0001), with reduced LVEF noted in 26.2% at FU<90%BL, in 13.5% at FU

Japanese registry for Mechanically Assisted Circulatory Support: First report.

BACKGROUND: In Japan, ventricular assist devices (VADs) have been used for patients with severe heart failure as a bridge to transplantation (BTT) since 1992. However, it was not until 1997, when the Organ Transplant Law was enacted, that medical devices received approval by the national health insurance system for that use. To encourage research and development of innovative medical devices, the Pharmaceuticals and Medical Devices Agency has established a public-private partnership in collaboration with academic societies, hospitals and manufacturers. METHODS: The Japanese registry for Mechanically Assisted Circulatory Support (J-MACS) is a prospective registry designed to be harmonized with the Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS). Participation in J-MACS is mandatory for device manufacturers to meet the conditions of approval as well as for hospitals to obtain authorization for reimbursement from the national health insurance system. RESULTS: From June 2010 to April 2015, 476 patients were registered at 31 hospitals. Of these, analysis of primary VAD patients (n = 332) revealed that their overall 360-day survival was 91% (implantable 93%, extracorporeal 84%). CONCLUSIONS: This initial report from J-MACS focuses on patients' demographics, device types, survival, competing outcomes, adverse events and successful examples of system failure detection.

Association between accessibility to emergency cardiovascular centers and cardiovascular mortality in Japan.

OBJECTIVE: The aim of this study was to examine the association between accessibility to cardiovascular emergency centers and cardiovascular mortality in Japan. DESIGN: A semi-ecological study. SETTING: Three databases were generated: accessibility to emergency cardiovascular centers, population records and death records. MAIN OUTCOME MEASURES: The standardized mortality ratio (SMR) for cardiovascular disease was adjusted by age and sex. Accessibility was represented by transfer time, number of cardiovascular emergency hospitals, and the proportion of habitable areas. Combinations of the three were divided into Categories 1-8 from the worst to the best, and the association with SMR was analyzed. RESULTS: There were 1998 cardiovascular emergency hospitals. The median of crude mortality was 0.16%. The median SMR of the reference Category 8 (transfer time <30 min and habitable area ≥50% with cardiovascular emergency hospitals) was 0.96, but that of the low accessibility Category 1 (transfer time ≥30 min and habitable area <50% without cardiovascular emergency hospitals) was 1.10. The SMR of accessibility Category 1 : Category 8 was 1.18 (95% confidence interval: 1.14-1.21). CONCLUSIONS: Decreased accessibility to cardiovascular emergency hospitals was associated with increased SMR. Areas with less accessibility and higher cardiovascular mortality were characterized by geographical variability in Japan.