Association of Life’s Simple 7 with incident cardiovascular disease in 53 974 patients with cancer

Abstract

Aims

Cancer survivors have a greater risk of cardiovascular disease (CVD). Although Life’s Simple 7 is used for CVD risk stratification in a general population, its utility in cancer survivors remains unknown. We aimed to clarify the association of Life’s Simple 7 with incident CVD among cancer survivors. Furthermore, we analyzed the relationship between the change in Life’s Simple 7 and the subsequent CVD risk.

Methods and results

This retrospective observational study was conducted using the JMDC Claims Database, and we analyzed 53 974 patients with a prior history of breast, colorectal, or stomach cancer, which is a common cancer site in the Japanese population. The median age was 54 years, and 37.8% were men. We modified the original definition of Life’s Simple 7 and identified the following ideal Life’s Simple 7 cardiovascular health metrics: non-smoking, body mass index < 25 kg/m², physical activity at goal, optimal dietary habits, untreated fasting plasma glucose < 100 mg/dL, untreated blood pressure < 120/80 mmHg, and untreated total cholesterol < 200 mg/dL. The primary endpoint was composite CVD outcome, including myocardial infarction, angina pectoris, stroke, and heart failure. Over a mean follow-up period of 975 ± 794 days, 3150 composite CVD outcomes were recorded. The risk of CVD events increased with a greater number of non-ideal Life’s Simple 7. The hazard ratio per 1-point increase in non-ideal Life’s Simple 7 was 1.15 [95% confidence interval (CI): 1.12–1.18). Furthermore, a 1-point increase in non-ideal Life’s Simple 7 over 1 year was associated with subsequent CVD risk (hazard ratio: 1.12, 95% CI: 1.06–1.19).

Conclusion

Life’s Simple 7 could be applicable for CVD risk stratification even among cancer survivors. Optimizing Life’s Simple 7 may prevent the development of CVD in cancer survivors.

Graphical Abstract

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See the editorial comment for this article ‘Cardiovascular health is the essential but overlooked aspect in the management of cancer survivors’, by Y. Ahn and M.-H. Jung, https://doi.org/10.1093/eurjpc/zwac241.

Introduction

The life expectancy and survival rates of patients with cancer are increasing owing to the development of effective screening, accurate diagnosis, and novel treatment strategies. In USA, there are an estimated 17 million cancer survivors, and the number of cancer survivors is predicted to continuously increase by >22 million by 2030.¹ Moreover, the survival of patients with cancer has improved owing to the progress in cancer treatment (e.g. molecular targeted therapy), and cardiovascular disease (CVD) in cancer survivors has become a critical clinical issue. Because CVD is the second most common cause of death in cancer survivors,² it is essential to stratify the risk of CVD in patients with cancer and take preventive measures. The American College of Cardiology/American Heart Association defined the Life’s Simple 7 cardiovascular health metrics according to seven modifiable risk factors and lifestyles, including smoking, body mass index, physical activity, dietary habits, blood pressure, fasting glucose level, and total cholesterol level, to reduce the burden of CVD in the general population.³ Previous studies have presented a robust relationship between Life’s Simple 7 and the incidence of CVD,^4–7 and it is considered a simple and informative evaluation method for the risk stratification of subsequent CVD events.⁸ However, there have been scarce data on the association of Life’s Simple 7 with the risk of developing CVD in patients with cancer. In this study, we selected three cancer types, including breast, colorectal, and stomach cancers, according to the incidence of cancers in the Japanese population (https://ganjoho.jp/reg_stat/statistics/stat/summary.html) and sought to clarify the relationship between Life’s Simple 7 and future CVD risk using a nationwide health check-up and administrative claims dataset. The original definition for Life’s Simple 7 was modified to fit our database. In particular, while the original definition used dietary components as a determinant of ideal eating habits, the present study defined it in terms of whether or not breakfast was skipped. Moreover, we analyzed the association of a 1-year change in Life’s Simple 7 with the subsequent risk of developing CVD. It is clinically essential to identify the risk stratification of CVD in patients with cancer when the importance of CVD in cancer survivors is increasingly recognized.

Methods

Anyone who purchases the JMDC claims database from JMDC Inc. (https://www.jmdc.co.jp/en/) can use this database.

Study population

We performed this retrospective observational cohort study using the JMDC Claims Database (Tokyo, Japan) between January 2005 and April 2021.^9–11 This dataset contains health check-up and administrative claims data collected from >60 insures. Claims data (e.g. cancer diagnosis, CVD diagnosis) were recorded according to the International Classification of Diseases, 10th Revision (ICD-10) codes. We extracted 59 253 individuals who were diagnosed with breast cancer (ICD-10: C50), colorectal cancer (ICD-10: C18–20), or stomach cancer (ICD-10: C16) and underwent a health check-up with available data for the assessment of Life’s Simple 7 after the diagnosis of cancer >1 year after the date of health insurance enrolment (1-year lookback period) (see Supplementary material online, Figure S1). The following records were excluded: 4850 individuals with a history of CVD, 44 individuals with a history of renal replacement therapy, and 385 individuals with missing data on alcohol consumption. Finally, 53 974participants were included in the study (see Supplementary material online, Figure S2).

Ethics

This study was performed in accordance with the ethical guidelines of the University of Tokyo (approval by the Ethical Committee of the University of Tokyo: 2018–10862) and the principles of the Declaration of Helsinki. As all data in the JMDC Claims Database were de-identified, the requirement for informed consent was waived.

Modified Life’s Simple 7 and other measurements

We modified the original definitions of AHA for Life’s Simple 7 to fit the database according to our previous studies.^9,10Supplementary material online, Table S1 lists the original definitions and the modified definitions used in this study. We assessed Life’s Simple 7 cardiovascular health metrics for each individual using health check-up records, which were almost uniform because a regular health check-up using a standardized format and protocol is mandatory for most Japanese employees. Ideal cardiovascular health metrics were set as follows: ideal body mass index was defined as <25 kg/m², ideal smoking status was defined as not smoking (never smoked or prior smoker), and current smoker was defined as smoking ≥100 cigarettes in a lifetime or smoking duration ≥6 months. Ideal physical activity was defined as 30 min of exercise at least twice a week or ≥1 h of walking per day. Ideal eating habits were defined as skipping breakfast <3 times per week. Ideal blood pressure was defined as an untreated blood pressure level of <120/80 mmHg, and ideal fasting plasma glucose level was defined as an untreated value of <100 mg/dL. We defined ideal total cholesterol level as an untreated value of <200 mg/dL. If the total cholesterol figures were not available, we calculated them using low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride measurements. We obtained data on cigarette smoking, physical activity, eating habit, and alcohol consumption using self-reported questionnaires during a health check-up.

Outcomes

We collected data on the outcomes that occurred between January 2005 and April 2021. We defined a composite endpoint that included myocardial (MI) (ICD-10 codes: I210–I214 and I219), angina pectoris (AP) (ICD-10 codes: I200, I201, I208, and I209), stroke (ICD-10 codes: I630, I631–I636, I638, I639, I600–I611, I613–I616, I619, I629, and G459), and heart failure (HF) (ICD-10 codes: I500, I501, I509, and I110) as the primary outcome. We analyzed each MI, AP, stroke, and HF event separately as a secondary outcome.

Statistical analysis

Descriptive statistics are presented as numbers (percentages) for categorical variables and medians (Q1–Q3) for continuous variables. The cumulative incidence of composite CVD events was calculated using the Kaplan–Meier method and compared between the numbers of non-ideal Life’s Simple 7 components using the log-rank test. Considering the small sample size of patients with no non-ideal Life’s Simple 7 components (n = 2 913) and seven non-ideal Life’s Simple 7 components (n = 100), we combined patients with 0 or 1 non-ideal Life’s Simple 7 component and those with 6 or 7 non-ideal Life’s Simple 7 components. CVD incidence was calculated per 10 000 person-years. We performed Cox regression analyses to assess the association between Life’s Simple 7 and CVD risk. Hazard ratios (HRs) were calculated in an unadjusted model (Model 1), an age–sex-adjusted model (Model 2), and after adjustment for potential confounders, including age, sex, alcohol consumption, cancer site, and active cancer treatment before and after 6 months (Model 3). Moreover, we conducted Cox regression analyses to identify the relationship between each Life’s Simple 7 component and CVD development. Model 1 included seven components. Model 2 included seven components, age, and sex. Model 3 included seven components, age, sex, alcohol consumption, cancer site, and active cancer treatment before and after 6 months.

To evaluate the association between 1-year change in Life's Simple 7 and the risk of developing CVD, we excluded the following individuals from the primary analysis: those who had missing data for calculating Life’s Simple 7 cardiovascular health metrics at 1 year after the initial health check-up (n = 20 223), and those who had CVD events within 1 year after the initial health check-up (n = 638). Finally, 33 113 secondary analyses were performed. We conducted Cox regression analyses to examine the association between the number of changes in Life’s Simple 7 over 1 year and a risk for CVD.

Six sensitivity analyses were conducted. First, death could be a competing risk for CVD events; therefore, we conducted a competing risks analysis using the Fine–Gray proportional sub-distribution hazards model. Second, we performed multiple imputations for missing data based on the assumption of missing data at random, as previously described.^12,13 HRs and standard errors were calculated using Rubin’s rules. Third, the induction period was set at 1, 2, and 3 years to minimize the potential influence of latent CVD. Fourth, to eliminate the influence of medications on the risk of CVD, we excluded patients taking blood pressure-, glucose-, or lipid-lowering medications at baseline. Fifth, subgroup analyses were conducted based on age (age ≥ 50 years vs. age < 50 years), sex (men vs. women), active cancer treatment (surgical treatment, chemotherapy, radiation therapy), and cancer sites. We excluded 1147 patients with multiple (two or three) cancers from a subgroup analysis stratified by cancer sites. P-values for the interactions were calculated using a multivariable model. Sixth, Life’s Simple 7 was recently upgraded to Life’s Essential 8.¹⁴ In this update, ‘sleep’ was included as an additional component. Therefore, we added a sleep component to the Life’s Simple 7. We obtained information regarding restfulness from sleep from questionnaires in the individuals’ health check-up records as previously described.¹⁵ If a study individual answered ‘YES’ to the following question, ‘Do you have a good rest with sleep?’ then this individual was categorized as having good restfulness from sleep. If a study individual answered ‘NO’ to this question, then this individual was categorized as having poor restfulness from sleep. We defined ‘having good restfulness from sleep’ as ‘ideal sleep’. Then, we calculated modified ‘Life’s Essential 8’.

Statistical significance was set at P < 0.05. Statistical analyses were conducted using STATA (StataCorp LLC, College Station, TX, USA).

Results

Baseline characteristics

The baseline clinical characteristics are presented in Table 1. Among the study population, 25 269(46.8%), 18 627 (34.5%), and 11 235 (20.8%) participants had a history of breast, colorectal, and stomach cancers, respectively (1137 patients had a history of two cancers and 10 patients had a history of three cancers). The median age was 54 (Q1–Q3 48-61) years and 20 386 participants (37.8%) were male patients. The median number of non-ideal cardiovascular health metrics was 3 (Q1–Q3 2–4).

Association between Life’s Simple 7 and cardiovascular events

During a mean follow-up period of 975 ± 794 days, 3150 composite CVD events were recorded. The cumulative incidence of composite CVD events increased with the increasing number of non-ideal Life's Simple 7 components (log-rank P < 0.001) (Figure 1). In a multivariable-adjusted model (Model 3), the number of non-ideal Life's Simple 7 components was associated with the risk of developing composite CVD events; the HR [95% confidence interval (CI)] of per 1-point increase in the number of non-ideal Life’s Simple 7 components for composite CVD events was 1.15 (1.12–1.18) (Figure 2).

Association between each Life’s Simple 7 component and cardiovascular events

Figure 3 shows the association between each Life’s Simple 7 component and the risk of developing composite CVD events. HRs (95% CI) of non-ideal status for smoking, body mass index, physical activity, dietary habits, blood pressure, fasting plasma glucose level, and total cholesterol level in the multivariable-adjusted model (model 3) were 1.04 (0.93–1.15), 1.16 (1.07–1.27), 1.11 (1.03–1.19), 1.08 (0.96–1.21), 1.39 (1.28–1.51), 1.16 (1.07–1.25), and 1.03 (0.96–1.12), respectively.

Association between Life’s Simple 7 and secondary cardiovascular events

The relationship between Life’s Simple 7 and the risk of developing secondary CVD events is summarized in Supplementary material online, Figure S3. The number of non-ideal status of Life’s Simple 7 was associated with MI, AP, stroke, and HF. Furthermore, HRs (95% CI) of per 1-point increase in the number of non-ideal Life’s Simple 7 components for MI, AP, stroke, and HF were 1.18 (1.04–1.35), 1.13 (1.08–1.18), 1.17 (1.11–1.24), and 1.17 (1.13–1.22), respectively.

Sensitivity analysis

First, 322 died during follow-up, and we calculated the subhazard ratios of the number of non-ideal Life’s Simple 7 components with incident composite CVD endpoints to account for the competing risks of death. The results with and without the use of competing risk models did not change, as shown in Supplementary material online, Figure S4. Second, we analyzed 54 359 patients after multiple imputations for missing data, and the relationship between Life’s Simple 7 and the composite CVD endpoint was consistent with our primary analysis (see Supplementary material online, Figure S5). Third, when we set an induction period of 1, 2, and 3 years, the number of non-ideal Life’s Simple 7 components was associated with a greater risk of developing CVD events (see Supplementary material online, Figure S6). Fourth, the relationship between Life’s Simple 7 and CVD outcomes remained unchanged after excluding 13 996 patients taking BP-, glucose-, or lipid-lowering medications (see Supplementary material online, Figure S7). Fifth, a stepwise increase in the risk of developing CVD with an increasing number of non-ideal Life’s Simple 7 components was observed in participants aged ≥50 and < 50 years, male patients, female patients, those with and without active treatment for cancers, and those with breast, colorectal, and stomach cancers. None of the P-values for the interactions were statistically significant (see Supplementary material online, Figure S8). Sixth, we analyzed 53 628 patients with available data on restfulness from sleep and 3 112 patients developed CVD. The risk of developing CVD increased with the number of non-ideal Life’s Essential 8 (see Supplementary material online, Figure S9). Non-ideal status of restfulness from sleep was associated with a greater risk of developing CVD (see Supplementary material online, Figure S10).

Association between changes in Life’s Simple 7 and the subsequent cardiovascular events

We analyzed 33 113 patients to examine the association between changes in Life’s Simple 7 scores and the risk of developing composite CVD events. A 1-point increase in the number of non-ideal Life’s Simple 7 components over one year was associated with an increased risk for the subsequent development of CVD events (HR: 1.12, 95% CI: 1.06–1.19) after adjusting for the baseline number of non-ideal Life’s Simple 7 components, age, sex, alcohol consumption, cancer site, and active cancer treatment before and after 6 months.

Discussion

The present study included 53 974 patients with a history of breast, colorectal, or stomach cancer and demonstrated that the incidence of composite CVD events increased with the number of non-ideal Life’s Simple 7 cardiovascular health metrics. This relationship between Life’s Simple 7 and incident CVD has been observed even in patients receiving active treatment for cancer. A 1-year change in Life’s Simple 7 was also associated with a subsequent risk of developing CVD. To date, this study is the first large-scale epidemiological study to uncover the relationship of Life’s Simple 7 with incident CVD among cancer survivors.

Patients with cancer are known to have a greater risk of developing CVD. Although various factors, including shared risk factors¹⁶ and cardiovascular toxicity due to cancer treatments,¹⁷ have been suggested to explain the increased risk of developing CVD among cancer survivors, there have been scarce data on the CVD risk stratification of patients with cancer. Among the general population, Life’s Simple 7 cardiovascular health metrics³ are known to stratify the future risk of developing CVD. For example, Yang et al.⁴ studied the National Health and Nutrition Examination Survey population and found that a higher Life’s Simple 7 score was associated with a lower all-cause and CVD mortality. Gaye et al.⁵ analyzed 9294 individuals aged ≥65 years and indicated that greater cardiovascular health metrics status was related to lower mortality and incidence of vascular events in the older adult population. Using the Coronary Artery Risk Development in Young Adults Study data, Perak et al.¹⁸ reported that a higher Life’s Simple 7 status in late adolescence or young adulthood was associated with a lower incidence of CVD events. Thus, the Life’s Simple 7 cardiovascular health metrics are considered a simple and informative assessment tool for the subsequent CVD risk.⁸ Despite the accumulation of clinical data on the association of Life’s Simple 7 with incident CVD among a variety of the general population, little was known regarding the relationship of Life’s Simple 7 with incident CVD among cancer survivors.

Our study is distinguishable from previous studies in that we found a positive association between a greater number of non-ideal Life’s Simple 7 components and an increased risk of developing CVD in patients with cancer. We confirmed the robustness of our primary findings using a multitude of sensitivity analyses. Moreover, the change in Life’s Simple 7 was associated with subsequent CVD risk among patients with cancer, suggesting the potential to ameliorate the status of modifiable risk factors to prevent the development of CVD in cancer survivors.

Three points should be noted for clinical implications

First, among Life’s Simple 7, blood pressure, fasting glucose level, body mass index, and physical (in)activity were independently associated with the future risk of incident CVD among cancer survivors. Considering the established roles of these factors in CVD development, these results are plausible. Although cachexia and malnutrition are a concern in patients with cancer, it is important that a higher body mass index was associated with incident CVD in patients with cancer, suggesting the clinical significance of both cachexia/malnutrition and obesity in these patients. It is also convincing that maintaining physical activity is associated with a lower risk of CVD. Although the relationship between cigarette smoking and incident CVD was not statistically significant, smoking cessation was recommended for patients with cancer irrespective of CVD risk.

Second, the number of non-ideal Life Simple 7 components was associated with a greater risk of CVD development, irrespective of the presence of active treatment for cancer. Although the management of modifiable risk factors and the assessment of CVD risk are prone to be neglected in patients undergoing active cancer treatment, our results suggest the importance of CVD risk evaluation using Life’s Simple 7, even in patients undergoing cancer treatment. Similarly, in the field of onco-cardiology, cardiologists tend to focus on the risk of specific conditions in patients with cancer (e.g., deep vein thrombosis and cancer therapeutics-related cardiac dysfunction), and the findings of the present study emphasize that it is important for cardiologists to manage not only the risk of specific adverse events in cancer survivors but also evaluate the status of modifiable risk factors and general cardiovascular risk (based on Life’s Simple 7) and provide appropriate preventive interventions for patients living with cancer.

Third, owing to the nature of the retrospective observational study design, the causal association between Life’s Simple 7 and CVD could not be concluded in this study. Nevertheless, considering that not only baseline Life’s Simple 7 but also its 1-year change was associated with the risk of subsequent CVD events, we believe that our results suggest the potential of optimizing Life’s Simple 7 for CVD prevention in patients with cancer. Further investigations (well-designed prospective studies or randomized clinical trials) are required to clarify this point and identify the optimal preventive strategy for CVD events in cancer survivors.

This study has several limitations which are mainly due to the use of this dataset as we previously discussed earlier.^9–11 We performed a multivariable Cox regression analysis. However, there could be unmeasured confounders and residual bias (e.g., socioeconomic status). The original definition of Life’s Simple 7 cardiovascular health metrics determines eating habits based on dietary components (the DASH diet), as shown in Supplementary material online, SupplementaryTable S1. Unfortunately, information on dietary components was not available in the JMDC Claims Database. Since skipping breakfast is known to be associated with a higher risk of developing CVD, we defined ideal eating habits as not skipping breakfast. We selected three cancer types because the prevalence of these cancers is common in Japan according to the national cancer statistics (https://ganjoho.jp/reg_stat/statistics/stat/summary.html), and our primary results were consistent across all subgroups (including cancer sites). However, it remains unknown whether our findings could be applicable to patients with other cancer types (particularly, cancer with poor survival rates). The incidence of CVD events in the JMDC Claims Database is comparable to that in other epidemiological datasets in Japan,^19,20 and the accuracy of recorded diagnoses (including CVD) in an administrative claims database has been reported to be high.^21,22 Therefore, we believe that our data could reflect real-world clinical settings in Japan. Nevertheless, recorded diagnoses in the administrative claims database should generally be considered less well-validated, and therefore, there remains uncertainty regarding the accuracy of CVD diagnoses. Given that the JMDC Claims Database mainly includes working-age population, whether the findings of this study could be generalized remain unclear and further investigations using other independent datasets are needed. Detailed information on cancer (i.e., cancer stage) was unavailable in our dataset. Although the relationship between Life’s Simple 7 and the risk of future CVD was unchanged in a competing risks model, the severity of cancer may have affected our results. The JMDC Claims Database does not include data on the cause of death (e.g., CVD or non-CVD death). We collected information on cigarette smoking, physical activity, eating habit, and alcohol consumption from self-reported questionnaires at health check-ups, and acknowledge that this subjective method is a study limitation. The observational period of the present study was relatively short, and therefore, our results need to be validated using other datasets with a longer follow-up. Although we presented the potential association of Life’s Simple 7 with incident CVD among cancer survivors, there remains various issues to be clarified. For example, our results showed that non-ideal Life’s Simple 7 would increase the risk of CVD among cancer survivors. However, its consequence in cancer survivors remains unclear. There have been so far scarce epidemiological data on the relationship of CVD with outcomes of cancer survivors. We need to accumulate more epidemiological data to move the field of onco-cardiology forward.

In conclusion, our analysis of >50 000 patients with a history of cancer demonstrated that Life’s Simple 7 cardiovascular health metrics could be used for the risk stratification of future CVD events in cancer survivors. Moreover, 1-year change in Life’s Simple 7 was associated with subsequent CVD risk. Our results confirm the clinical significance of maintaining modifiable risk factors in CVD development among cancer survivors and suggest the potential clinical benefit of optimizing Life’s Simple 7 for CVD prevention in patients with cancer. Our results suggests the importance of multidisciplinary cooperation (e.g., oncologists, cardiologists, general physicians) to improve clinical outcomes of cancer survivors.

Author Contributions

H.K., A.O., K.F., K.N., H.Y., and I.K. contributed to the conception and design of this work. Y.S., K.U., A.O., S.M., N.M., T.J., and H.Y. contributed to the analysis of the data for this work. H.K., A.O., K.F., N.T., H.M., K.N., H.Y., and I.K. contributed to the interpretation of the data. H.K., A.O., Y.S., N.T., H.M., and H.Y. drafted the manuscript. N.T., H.M., K.N., H.Y., and I.K. contribute to the critical revision for important intellectual content. All authors gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Supplementary material

Supplementary material is available at European Journal of Preventive Cardiology online.

Funding

This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (19AA2007 and H30-Policy-Designated-004), and the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141).

IRB information

Name of the ethics committee: the Clinical Research Review Board of The University of Tokyo [2018–10862].

Data availability

The JMDC Claims Database is available for purchase from JMDC Inc. (https://www.jmdc.co.jp/en/).

References

Author notes