Clinical evaluation and outcome in heart failure patients receiving chemotherapy with different anti-cancer agents.

Introduction

Heart failure (HF), a clinical syndrome associated with considerable morbidity and mortality, reduced quality of life (QOL) and financial burden, remains a major clinical and public health problem. 1 The common aetiologies are ischaemic heart disease, hypertension, valvular disease and drugs (e.g., anti‐cancer agents). The 5 and 10 year survival rates of HF patients are estimated to be 57% and 35%, respectively. 2 Although the majority of patients with HF previously died of cardiovascular (CV) causes, non‐CV deaths have been increasing recently, mainly because of an increase in cancer‐related deaths. 3

Over the last few decades, advances in cancer therapy have prolonged the life expectancies of patients diagnosed with malignancies. Although traditional cytotoxic chemotherapy, molecularly targeted therapy and immunotherapy have improved the survival rates, 4 off‐target adverse effects (AEs), such as complications of the CV system, require attention. In particular, immune checkpoint inhibitors (ICIs) lead to acute HF and even death caused by various mechanisms such as myocarditis and arrhythmia. 5 The field of cardio‐oncology has received increasing attention because of the problem of cardiotoxic effects of anti‐cancer therapies. 6

The optimal strategy for modern chemotherapy is based on a comprehensive approach for patients in oncology and cardiology. Therefore, medical providers should carefully assess and monitor patients with cancer before, during and after chemotherapy. Currently, the need of the patient is to address any predisposing risk factors, prevent, identify early and properly treat the acute, chronic and late‐onset CV toxicity of cancer treatment, and manage and improve the QOL of cancer survivors with CV AEs. 7 , 8

Recently, some studies have reported trastuzumab‐related cardiotoxicity using claims databases reported from Asia. 9 , 10 , 11 However, the influence of different anti‐cancer agents on clinical outcomes in patients with HF is unknown. Therefore, we aimed to investigate the prescription of anti‐cancer agents before and after treatment in patients with HF in the Japanese Registry of All Cardiac and Vascular Diseases (JROAD) and evaluate the clinical characteristics and outcomes of patients with HF who received chemotherapy compared with a matched cohort with HF not receiving chemotherapy, using real‐world registry data of HF.

Methods

Study population

This study was approved by the Showa University Research Ethics Review Board (approval number: 22‐084‐B). The study population comprised patients hospitalized from April 2012 to March 2021 as per the JROAD Diagnosis Procedure Combination (DPC) database. The JROAD‐DPC is a nationwide registry medical database with information on admission and discharge for CV disease, clinical characteristics and treatment status, patient status and hospital overview. The JROAD‐DPC database integrates information from the JROAD‐DPC data with analysis datasets covering 11 million cases in 1119 hospitals between April 2012 and March 2021. The identification of HF and cancer was based on the International Classification of Diseases, Tenth Revision (ICD‐10) diagnosis codes (Table S1 ). Data on patient age, sex, main comorbidities at admission, length of hospitalization and treatment content were extracted from the database. We included 1 328 113 patients who were hospitalized for HF (Figure 1 ), of which 59 229 patients (4.46%) had cancer. We excluded 14 043 patients with unknown outcomes, non‐emergency admissions and unknown chemotherapy data. Consequently, 5774 patients who received chemotherapy and 39 412 patients who did not receive chemotherapy were included in the readmission assessment. The chemotherapy group is classified into three groups (oral, transvenous or transarterial, and other) in the DPC database.

We investigated the treatment before hospitalization and at discharge. Anti‐cancer agents of chemotherapy included ICIs, human epidermal growth factor receptor 2 (HER2) inhibitors, anti‐vascular endothelial growth factor receptor (VEGF) agents, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR‐TKIs), anaplastic lymphoma kinase (ALK) inhibitors, V‐Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors, c‐ros oncogene 1 (ROS1)/tropomycin receptor kinase (TRK) inhibitors, Janus‐activated kinase (JAK) inhibitors, fms‐like tyrosine receptor kinase 3 (FLT3) inhibitors, cyclin‐dependent kinase 4/6 (CKD4/6) inhibitors, poly‐ADP‐ribose polymerase (PARP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, immunomodulatory drugs (IMiDs), proteasome inhibitors, mitogen‐activated protein kinase kinase (MEK) inhibitors, fluorouracil agents, anthracyclines, taxanes or alkylating agents (Table S2 ). In addition, we investigated the use of hormone therapy to treat cancer before hospitalization. Hormone therapy included aromatase inhibitors, anti‐oestrogens, anti‐androgen, luteinizing hormone‐releasing hormone (LHRH) agonists and gonadotropin‐releasing hormone (GnRH) antagonists (Table S2 ).

Clinical outcomes

The primary outcome was 1 year of readmission for any cause. We compared the hospital mortality (30 days) between patients with HF who did or did not receive chemotherapy before and after propensity score (PS) matching.

Sample matching

PS matching reduced the confounding effects of differences in patient backgrounds, such as sex and cancer type. After matching the variables, 11 532 patients with HF in the chemotherapy and non‐chemotherapy groups were included in the final analyses. The concordance index was 0.85 (Figure S1 ), and the consistency of the PS densities was confirmed after matching the variables (Figure S2 ). The balance of each covariate between the two groups before and after matching was evaluated using standardized differences. Match quality was determined using standardized mean differences (SMDs). The absolute value of the standardized differences <0.1 was considered a relatively small imbalance.

Statistical analysis

PS was estimated with a logistic regression model, with chemotherapy as the dependent variable and the following 27 clinically relevant covariates: age, sex, hospitalization days, comorbidities (hypertension, diabetes mellitus, dyslipidaemia, stroke, myocardial infarction, peripheral vascular disease, cerebrovascular disease, rheumatic disease, chronic kidney disease, liver failure, chronic obstructive pulmonary disease, dementia and metastatic cancer) and treatment [loop diuretics, thiazide diuretics, tolvaptan, angiotensin‐converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), renin, beta‐blocker, αβ‐blocker, mineralocorticoid receptor antagonist (MRA), angiotensin receptor–neprilysin inhibitor and sodium–glucose cotransporter 2 inhibitors]. Matching was performed using the nearest neighbour method, with a calliper of width 0.2 standard deviations of the logit of the estimated PS. After matching, we estimated the odds ratio (OR) and 95% confidence interval (CI) for readmission within 1 year. Furthermore, we analysed subgroups according to the type of chemotherapy administered in the PS‐matched cohort. The OR for each type of anti‐cancer drug was calculated using matched patients who did not receive chemotherapy as the controls. Further, we calculated the readmission rates for the oral, transvenous/transarterial and other groups as classified in the DPC database using Pearson's chi‐squared test. All statistical tests were two‐sided, and values <0.05 were considered statistically significant. Statistical analyses were performed using JMP Pro Version 16.0 (SAS Institute Inc., Cary, NC, USA), R Version 4.3.2 and RStudio Version 2023.09.1‐494.

Results

The proportion of type of cancer in hospitalized patients with HF

We calculated the proportion of each cancer type among patients with HF during the first hospital admission (Figure 2 ). Colon, lung, breast and prostate cancers accounted for >60% of all cancers. The proportion of prostate cancer, bladder cancer and leukaemia in this study was two times more than national statistics. 12 In contrast, this study's proportion of stomach cancer was seven times less than the national statistics. After PS matching, 62.5% and 19.5% of patients with HF had prostate and breast cancers, respectively.

The proportion of each anti‐cancer agent before hospitalization and at discharge

The proportion of each anti‐cancer agent used before hospitalization and at discharge was calculated (Table 1 ). LHRH agonists, anti‐androgens, fluorouracil agents and EGFR‐TKIs accounted for more than 50% of the total anti‐cancer agents administered before hospitalization. On the other hand, oral anti‐cancer agents such as EGFR‐TKIs, JAK inhibitors and endocrine therapy were associated with a higher continuation rate than that with injection anti‐cancer agents at discharge.

Patient characteristics

We found the patient characteristics before and after PS matching (Table 2 ). In the group before PS matching ( n = 45 186), 64.4% ( n = 32 453) were male, with a median age of 82 years (range: 20–106 years). In total, 5774 patients received chemotherapy, and 39 412 did not. Before PS matching, the number of males was higher in the chemotherapy group than in the non‐chemotherapy group. Loop diuretics, tolvaptan, ACE inhibitor, ARB, beta‐blocker, αβ‐blocker and MRA for HF treatment during hospitalization were higher in the group with chemotherapy than without chemotherapy. In addition, the incidences of liver cancer, colon cancer, lung cancer, bladder cancer and non‐Hodgkin lymphoma were lower in the chemotherapy group than in the non‐chemotherapy group. In contrast, the incidences of breast cancer, prostate cancer and leukaemia were higher in the chemotherapy group than in the non‐chemotherapy group. The median length of hospitalization was slightly longer in the chemotherapy group than in the non‐chemotherapy group.

After PS matching, 33 654 patients were excluded, and 11 532 patients were included in the analysis. In the matched cohort, there were no significant differences between the groups of patients with and without chemotherapy in terms of age, sex, comorbidities or HF treatment.

Outcomes

After PS matching, HF patients with chemotherapy significantly increased in 1 year of readmission risk compared with matched patients without chemotherapy (OR, 1.26; 95% CI 1.17–1.36, P < 0.01) (Figure 3 ). However, after PS matching, HF patients who received chemotherapy had lower chances of hospital mortality (30 days) than patients without chemotherapy (4.2% vs. 7.7%, P < 0.01) (Table 3 ).

Relation between readmission within 1 year and types of anti‐cancer agents

The ORs for the readmission in the case of each anti‐cancer agent are shown in Figure 3 . Patients treated with EGFR‐TKIs, JAK inhibitors, IMiDs, fluorouracil agents, anthracyclines, taxanes and alkylating agents before hospitalization had significantly higher readmission rates than matched patients who did not receive chemotherapy (EGFR‐TKIs: OR, 1.69; JAK inhibitors: OR, 4.92; IMiDs: OR, 13.4; fluorouracil agents: OR, 1.65; anthracyclines: OR, 1.86; taxane: OR, 2.95; and alkylating agents: OR, 1.35). In contrast, patients taking anti‐VEGF agents, ICIs and HER2 inhibitors before hospitalization showed no significant difference in readmission compared with matched patients who did not receive chemotherapy (anti‐VEGF agents: OR, 1.39; ICIs: OR, 1.56; and HER2 inhibitors: OR, 1.39). Patients treated with aromatase inhibitors, anti‐androgens, LHRH agonists and GnRH antagonists before hospitalization had significantly higher readmission rates than matched patients who did not receive chemotherapy (aromatase inhibitors: OR, 1.40; anti‐androgens: OR, 1.39; LHRH agonists: OR, 1.18; and GnRH antagonists: OR, 2.17). The readmission rates were 2629/4732 (55.6%) for the oral group, 351/612 (57.4%) for the transvenous or transarterial group, and 235/422 (55.7%) for the other group ( P = 0.68).

Discussion

The main findings of the study were as follows: (1) Prostate and breast cancers were more prevalent among patients with HF after PS matching because prostate and breast cancers have better survival rates compared with other cancers. (2) Patients with HF who received chemotherapy had a significantly higher risk of readmission within 1 year than those who did not receive chemotherapy. However, in the case of hospital mortality, patients who received chemotherapy were at lower risk than patients who did not receive chemotherapy. (3) Patients with HF and cancer who were administered EGFR‐TKIs, JAK inhibitors, IMiDs, fluorouracil agents, anthracyclines, taxane or alkylating agents had a significantly higher risk of readmission within 1 year than those who did not receive chemotherapy. (4) Patients with HF and cancer receiving endocrine therapy such as aromatase inhibitors, anti‐androgens, LHRH agonists and GnRH antagonists had a significantly higher risk of readmission within 1 year. This study is the first to assess the relationship between chemotherapy and readmission risk in a large‐scale cohort of patients with HF.

Patient characteristics and impact of prescription rate of anti‐cancer agents before hospitalization and at discharge

The median age was higher than that of the general HF population in this study, and patients with HF and cancer were more likely to have prostate and breast cancers after PS matching. This higher likelihood of having prostate and breast cancers is because of their better prognosis and survival compared with other cancers. The prescription rates of anti‐cancer agents before hospitalization were high for EGFR‐TKIs, fluorouracil agents, alkylating agents, taxanes and endocrine therapies. The type of cancer, including prostate, colon, lung and breast cancers, and its treatment influenced the results. On the other hand, at discharge, the continuation rates of oral anti‐cancer agents were high regarding EGFR‐TKIs and endocrine therapies, while injection anti‐cancer agents were discontinued. We suggested that injection anti‐cancer agents were difficult to be re‐administered because they might lead to acute toxicity such as febrile neutropenia (FN), whereas oral anti‐cancer agents rarely caused it.

Impact of chemotherapy on HF

After PS matching, readmission within 1 year in patients with HF receiving chemotherapy was significantly higher than that in matched patients who did not receive chemotherapy. Patients with HF are increasing dramatically because of an ageing population. 13 In addition, over the last few decades, there has been a remarkable improvement in the life expectancy of patients diagnosed with malignancies because of advances in cancer therapy. Therefore, patients with HF undergoing chemotherapy may have a high risk of readmission because of complicated long‐term care management. In addition, these patients often experience serious AEs during chemotherapy. FN is a commonly encountered medical emergency in patients undergoing chemotherapy, and it needs to be managed in a hospital. 14 Nevertheless, we observed that hospital mortality is lower in patients with HF receiving chemotherapy compared with those who did not receive chemotherapy. The American Society of Clinical Oncology guidelines recommend against the use of chemotherapy in patients with solid tumours who have not benefited from prior treatment and have an Eastern Cooperative Oncology Group performance status score of 3 or more. 15 Therefore, a proportion of non‐chemotherapy patients might be included in the best support care (BSC) for patients with HF and cancer.

Impact of anti‐cancer agents on readmission

Fluorouracil agents are anti‐cancer agents used in treating different types of solid malignancies. 16 Our study included fluorouracil agents mainly for breast, colon and lung cancers. Fluorouracil cardiotoxicity is reversible in most cases, and management includes discontinuation of the drug and use of guideline‐directed medical therapy. 17 We observed that patients with HF who received fluorouracil agents before hospitalization were at higher risk of admission than patients with HF who did not receive chemotherapy. Chemotherapy in patients with breast cancer does not include only fluorouracil, but it is mainly combined with anthracycline, such as fluorouracil + epirubicin + cyclophosphamide (FEC) therapy. 18 Although combination with anthracycline may influence the outcome, we cannot discuss the readmission risk of combination chemotherapy in our study.

Anthracyclines are key drugs for adjuvant chemotherapy of breast cancer and are used in the treatment of different types of childhood cancer. However, they cause cardiotoxic effects associated with ventricular dysfunction. 19 , 20 In our cohort, anthracyclines were administered mainly to patients with breast cancer. Serial monitoring of left ventricular (LV) ejection fraction (LVEF) while on anthracycline treatment demonstrates a cumulative percentage of significant LV systolic dysfunction of ≥7% at 200 mg/m 2 , ≥16% at 400 mg/m 2 , ≥20% at 500 mg/m 2 and ≥2% at ≥550 mg/m 2 equivalent dosage. 21 When reduced LVEF develops, an irreversible cardiac injury may have potentially occurred. 22 , 23 We observed that patients with HF who received anthracyclines before hospitalization were at a higher readmission risk than those who did not receive chemotherapy. Therefore, we need to be careful when managing anthracycline‐induced HF.

Taxanes are key drugs for the chemotherapy of advanced cancers, such as breast and prostate cancers. In our study, taxanes were used mainly for breast and prostate cancers. Anti‐microtubule agents called taxanes are associated with treatment‐induced CV toxicity. 20 For chemotherapy in patients with breast cancer, taxanes are typically combined with anthracyclines, such as docetaxel, after adriamycin + cyclophosphamide (AC) therapy in adjuvant chemotherapy. 18 Although combination with anthracycline may influence the outcome, we cannot discuss the readmission risk of combination chemotherapy in our study.

EGFR inhibitors can be classified into three groups based on the type of cancer for which they are approved: afatinib for the treatment of non‐small cell lung cancer, lapatinib for the treatment of breast cancer and vandetanib for the treatment of other types of cancer, such as thyroid cancer. 24 , 25 The risk of HF is highest in the initial stages of therapy, with 33.8% of patients receiving sorafenib, sunitinib and pazopanib experiencing a cardiac event during treatment for metastatic renal cell carcinoma. 26 In addition, in a meta‐analysis of 29 000 patients with cancer, there was a 3.8‐fold higher relative risk of hypertension in those treated with a VEGF tyrosine kinase inhibitor (TKI) compared with control subjects. 27 TKI is the main antineoplastic drug involved in developing peripheral artery disease. 28 Our cohort mainly received EGFR‐TKIs for leukaemia and lung cancer. We identified that patients with HF who received EGFR‐TKIs before hospitalization had a higher risk of readmission than those who did not receive chemotherapy. As TKIs may continue even after discharge, medical providers must ensure careful monitoring and follow‐up.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anaemia and splenomegaly. The oral JAK1/JAK2 inhibitor tuxolitinib continues to be the standard of care for high‐risk MF. An increased risk of major adverse CV event (MACE) was observed in patients with rheumatoid arthritis receiving tofacitinib compared with those receiving tumour necrosis factor (TNF) blockers. 29 In contrast, a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database and the World Health Organization VigiBase database showed no disproportionality for MACE with ruxolitinib. 30 We observed that patients with HF who received JAK inhibitors before hospitalization were at a higher readmission risk than those who did not receive chemotherapy. However, it is unknown whether ruxolitinib, a JAK inhibitor, induces cardiotoxicity.

An increased incidence of stroke has been demonstrated in patients with multiple myeloma (MM) receiving IMiDs such as thalidomide, lenalidomide and pomalidomide. 28 Some of the IMiDs have been associated with cardiotoxicity, in addition to their well‐known increased risk of vascular complications, including venous thrombo‐embolism, among others. 31 Pharmacovigilance analysis of the FAERS dataset showed that the percentage of cardiac AEs attributable to atrial fibrillation was high in pomalidomide (23.9%) and lenalidomide (18.2%). 32 In addition, MM is indeed a disease prevalent in the elderly population, who inherently carry an increased risk of CV disease solely because of age. Therefore, cardiotoxicity might be influenced not only by drug‐induced factors but also by other elements, such as age.

Alkylating agents are key drugs for the chemotherapy of breast cancer, leukaemia and malignant lymphoma. We suggested that patients with HF who received alkylating agents before hospitalization have a higher readmission risk than those who did not receive chemotherapy. While cyclophosphamides are not typically categorized as chemotherapeutic drugs causing CV toxicity, 33 these agents are reported to induce hypertension 34 and may be linked to potentially adverse CV effects, including HF. Moreover, cyclophosphamide is combined with anthracycline, such as AC therapy for breast cancer. Therefore, alkylating agents may have potentially adverse CV effects, but there is also a need to consider confounding factors combined with anthracycline.

Patients with HF who received HER2 inhibitors were not significantly different in terms of readmission from those with HF who did not receive chemotherapy. However, it is recognized that anti‐HER2 therapies may lead to LV dilation in up to 15%–20% of patients. LV function surveillance is recommended before and every 3 months during HER2‐targeted therapy treatment. 33 A previous study reported that HER2 inhibitor‐induced cardiotoxicity was at least partly reversible in more than two thirds of the cases. 35 Although HER2 inhibitors might have less influence on readmission because of the recovery of cardiac function by temporary discontinuation, LV function surveillance is needed to continue, based on guidelines.

Patients with HF who received ICIs, anti‐VEGF agents, ALK inhibitors, CKD4/6 inhibitors, mTOR inhibitors and proteasome inhibitors were not significantly different in the case of readmission from those in patients with HF who did not receive chemotherapy. We acknowledge that the use of these agents was limited in our study. Moreover, although anti‐VEGF agents induce cardiotoxicity, 33 their effects may vary depending on the type of cancer and the prescribed dosage for the specific indication.

Impact of endocrine therapy on readmission

We observed that patients with HF receiving endocrine therapy have increased readmission rates compared with their counterparts not receiving chemotherapy. Prostate and breast cancers have a high 5 year survival rate in Japan and worldwide at 99.1% and 92.3%, respectively. 12 However, endocrine therapies such as aromatase inhibitors, anti‐androgens, LHRH agonists and GnRH antagonists require prolonged administration. 36 These agents induce hypertension 37 and are associated with potentially adverse CV effects, including HF. Recently, a study reported that aromatase inhibitors were associated with a higher risk of CV events. 38 Therefore, long‐term endocrine therapy may be more difficult to manage in patients with HF. Medical providers need to be more careful regarding high‐risk elderly patients with HF who are predicted to have cardiotoxicity. The European Society of Cardiology suggests that baseline clinical CV assessment, physical examination and electrocardiogram (ECG) are recommended in all cancer patients scheduled for cardiotoxic therapies. 33 Additional investigations, such as the monitoring of brain natriuretic peptide (BNP) levels, may be considered for the early detection of cardiotoxicity during endocrine therapy for patients with prostate and breast cancers.

Limitations

This study, which was based on ICD‐10 codes, has several limitations. First, we only analysed hospitalized patients with HF in the database, which may have resulted in a selection bias. Second, although we excluded patients with planned hospitalization, 1 year readmission for any cause was the outcome. We needed to consider readmission due to other causes such as CV events, because chemotherapy requires readmission for either receiving the next cycle of chemotherapy or dealing with side effects such as myelosuppression and infection. However, more than 80% of patients receive outpatient chemotherapy instead of inpatient chemotherapy at the DPC institutions in Japan. 39 In addition, adverse events in patients with cancer undergoing chemotherapy in Japan are managed better with various initiatives. 40 , 41 Emergency hospitalization rate in patients undergoing chemotherapy was 0.6% at the National Cancer Center Hospital East in Japan. 42 Some research suggested that outpatient care for low‐risk FN emergency patients could be provided safely and effectively. 43 , 44 In our study, the readmission rate for the three groups (oral, transvenous or transarterial, and other) after PS matching was similar. Acutely toxic chemotherapy is typically discontinued during hospitalization, while oral anti‐cancer drugs and hormone therapy are often continued, suggesting that hospitalization due to side effects of chemotherapy might be rare. However, we need to consider the detailed reasons for readmission in future studies, as adverse events such as FN caused by chemotherapy pose significant concerns. Third, regarding the diagnosis of HF, we could not classify ejection fraction (EF), such as reduced or preserved EF due to a lack of real‐world clinical and DPC data, and we did not know the details of HF, such as BNP and causes. However, we considered that PS matching could reduce the confounding effects of differences in therapies in patients with HF, and there was similarity regarding severity including, to some extent, EF. Fourth, we could not identify the number of patients who showed signs of HF but without the need for hospitalization. However, in Japan's universal healthcare system, very few patients with severe HF symptoms or HF that is judged by a physician to require hospitalization stay home for socioeconomic reasons. Conversely, patients who enter palliative care because of cancer may choose to remain in hospice or at home rather than be readmitted. Fifth, regarding chemotherapy, it is unclear how many people who did not receive chemotherapy account for BSC and treatments other than chemotherapy. Sixth, our results might limit the effectiveness of observations made in relation to other healthcare systems, ethnic groups and different cancer disease management due to the database created in Japan. Although we could not solve those limitations in this database, we suggest that our study might be a meaningful first‐stage report that would enable future development of research combining real‐world clinical data with DPC data.

Conclusions

Patients with HF who received chemotherapy such as EGFR‐TKIs, JAK inhibitors, IMiDs, fluorouracil agents, anthracyclines, taxanes, alkylating agents or endocrine therapy had a significantly higher risk of readmission within 1 year than those who did not receive chemotherapy. Medical providers need to monitor and follow‐up patients with HF depending on the characteristics of the anti‐cancer agents and types of cancer. In addition, close collaboration among oncologists, cardiologists and healthcare professionals will ensure the delivery of optimal care for patients with HF undergoing chemotherapy.

Conflict of interest statement

Tomiko Sunaga received personal fees from the Academic Subcommittee on Health Care and Pharmaceutical Sciences. Yoshitaka Iso received speaker fees from Novartis, Bayer, Toa Eiyo, Tsumura, Daiichi Sankyo, AstraZeneca and Viatris and received a joint research grant from NTT Communications. Mio Ebato received speaker fees from Novartis, Otsuka, Sanofi, Pfizer, Ono, Bayer, Sumitomo Pharma, AstraZeneca, Boehringer Ingelheim and Kowa and has received scholarship funds from Pfizer. Tsutomu Toshida received speaker fees from Daiichi Sankyo and Toa Eiyo. Shuichi Nawata received speaker fees from Pfizer, Daiichi Sankyo, Chugai, Bristol Myers Squibb and Qol and also received consulting fees from Afrac and payment for manuscript writing from Lilly. Hiroshi Suzuki received speaker fees from Novartis and Otsuka, scholarship funds from Abbott and Daiichi Sankyo, and a joint research grant from Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, received a contract for research from Ono Pharmaceutical Co., Ltd.

Funding

This work was partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI grant (Number 22K12895) given to T. Sunaga.

Supporting information

Figure S1. Receiver operating characteristic curve and concordance index.

Figure S2. Comparison the consistency of propensity score densities before and after matching.

Table S1. International Classification of Disease, Tenth Revision (ICD‐10) diagnosis codes of heart failure and cancer.

Table S2. Defined type of anti‐cancer agents.

Acknowledgements

This work was partly supported by the Foundation for Promotion of Cancer Research in Japan. The authors wish to thank Yoko Sumita and the participants of the JROAD study for their valuable contributions.

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