Cardiovascular risk factors during cancer treatment. Prevalence and prognostic relevance: insights from the CARDIOTOX registry

Abstract

Introduction

The control of major cardiovascular (CV) risk factors is strongly recommended for primary and secondary prevention of CV diseases, regardless of age and associated comorbidities.^1–3 Some CV risk factors, including hypertension, diabetes, and hypercholesterolaemia may increase during exposure to certain cancer therapies.^4–6 In cancer patients, CV risk factors identification and control may be neglected or not considered as a priority.⁷ The prevalence of CV risk factors in this population and its possible relationship with outcomes and cardiotoxicity (CTox) secondary to cancer treatment has not been studied in detail. The multicentre, prospective CARDIOTOX registry, including a relatively large cohort of cancer patients treated with high-risk chemotherapy for CV toxicity and followed for 2 years provides an opportunity to explore the prevalence of CV risk factors in this group of patients, as well as its relationship with CTox and outcomes, which constitute the main objectives of the present study.

Methods

Study design

The CARDIOTOX registry (Clinical trials identifier NCT02039622) is a prospective multicentre study aiming at identifying the factors related with risk of cancer therapy CTox.⁸ The study was approved by the ethical committees of the participating hospitals and all patients signed an informed consent.

Patients

A total of 1324 adult patients receiving cancer therapies previously associated with moderate/high risk for CV toxicity (reported incidence of severe CTox ≥2%) and with an expected life survival of more than 6 months were prospectively included in the registry, from April 2012 to October 2017. Details of the study patients and methods have been previously published.⁸ Clinical data and echocardiographic parameters were prospectively collected according to protocol, at baseline before cancer therapy and then at 3 weeks, 3 months, 6 months, 1 year, 1.5 years, and 2 years after initiation of cancer therapy.

A medical history of hypertension, diabetes, and hypercholesterolaemia was considered positive when there was a medical diagnosis according to the European Society of Cardiology (ESC) guidelines for CV risk prevention.^1,2 Per protocol, all patients were reassessed during the baseline visit in order to identify those who met ESC criteria for hypertension, diabetes, and hypercholesterolaemia that had remained undiagnosed prior to the inclusion in the study. History of smoking was considered as positive if the patients were currently smoking or quit between the time of this episode of cancer diagnosis and the inclusion in the registry.

All patients were followed by a cancer specialist and a cardiologist in a dedicated cardio-oncology clinic, and special care was given to the identification and control of CV risk factors. Study data were collected and managed using REDCap electronic data capture tools hosted at IdiPaz Research Institute, Madrid.⁹

Definitions

Hypercholesterolaemia was considered in presence of LDL cholesterol values above the recommended levels in the ESC guidelines^1,10 (>115 mg/dL in patients with low to moderate CV risk, >100 mg/dL in patients with high CV risk and >70 mg/dL in patients with very high CV risk); hypertension in presence of systolic blood pressure >140 mmHg or diastolic blood pressure ≥90 mmHg^1,2 and diabetes in presence of a fasting plasma glucose >126 mg/dL or HbA1c >6.6%.^1,3

Overall CV risk score was calculated using the Systemic Coronary Risk Estimation (SCORE) tables of the ESC.^1,11 Total CVR was estimated with the SCORE equation for low-risk regions, considering three categories: low to intermediate risk or SCORE <5%, high risk or SCORE 5–10%, and very high risk or SCORE ≥10%.

CTox was defined in presence of new or worsening myocardial damage/dysfunction during follow-up, from normal to mild moderate or severe, mild to moderate or severe or moderate to severe. CTox was classified as mild, moderate, or severe according to the worst myocardial injury/dysfunction observed during follow-up.⁸ According to this classification, severe CTox was characterized by clinical heart failure or asymptomatic systolic left ventricular dysfunction (left ventricular ejection fraction ≤ 40).

Statistical analysis

Baseline characteristics, including demographics, medical history, type of cancer, previous chemotherapy, and radiotherapy were summarized using mean and standard deviation for continuous variables and frequencies and percentages for categorical ones. Non-normal distributed continuous variables were summarized with medians and interquartile range. Differences between groups were tested with analysis of the variance or Kruskal–Wallis rank test for continuous variables and with the Pearson χ² or Fisher’s exact test for categorical data. Odds ratio for CTox was assessed using logistic regression. Event rates for all-cause mortality were calculated using Kaplan–Meier methods and hazard ratios (HRs) were estimated using proportional hazards Cox-regression analysis. An overall alpha-level of 0.05 was used as a cut-point for statistical significance and all statistical tests were two-sided. All data were analysed using STATA v.15 statistical software (StataCorp LLC. 2017. College Station, TX, USA).

Results

A total of 1324 consecutive patients with a mean age of 55.3 ± 14.3 years (80.5% women), were included in the study, the most prevalent cancer diagnosis being breast cancer (799 patients, 60.4%) followed by non-Hodgkin lymphoma (205 patients, 15.5%).

Prevalence of risk factors at baseline

Before chemotherapy, 893 patients (67.4%) presented at least one risk factor: 167 (12.6%) were current smokers, hypertension was present in 342 (25.8%), diabetes in 176 (13.3%), and hypercholesterolaemia in 639 (48.3%). Among these patients, 28 (2.1% of the whole cohort), 66 (5.0%), and 323 patients (24.4%) did not present a previous diagnosis, but they met guidelines criteria for hypertension, diabetes, and hypercholesterolaemia during the baseline visit, prior to receiving chemotherapy. Among all four major risk factors groups, breast cancer and treatment with anthracyclines remained the most prevalent pathological baseline characteristics. Supplementary material online, Table S1 details the demographic information for these subgroups.

One CV risk factor was present in 545 patients (41.2%), 2 in 271 (20.5%); 3 in 71 (5.4%), and 4 in 6 patients (0.5%). The number of risk factor increased progressively with age (Supplementary material online, Table S2). Data contained in the registry database allowed us to estimate the SCORE risk at baseline in 1287 patients (96.0%). Among this population, 1040 patients (80.8%) presented a low to intermediate SCORE risk (0–4), 213 (16.6%) high SCORE risk (5–9), and 34 (2.6%) a very high SCORE risk (≥10) (Supplementary material online, Figure S1). Median calculated CV risk SCORE punctuation was 1; (ICR 0–3, range 0–15). Further data regarding baseline characteristics in patients with low to intermediate, high and very high SCORE risk are shown in Table 1.

Treatments to control risk factors

Data regarding the use of angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin II receptor blockers (ARBs), betablockers, aspirin, and statins, commonly recommended for treatment of risk factors and prevention of CV disease are detailed in Table 2. The proportion of patients receiving ACE-I/ARBs, betablockers, statins, diuretics, calcium channel blockers, and antiplatelet therapy was significantly increased during follow-up.

Evolution of risk factors during follow-up

The proportion of patients with poor control of major CV risk factors according to the therapeutic targets specified in the ESC guidelines, at baseline and after the initiation of chemotherapy, is illustrated in Figure 1. The cumulative diagnosis of hypertension, diabetes, and hypercholesterolaemia is illustrated in the Supplementary material online, Figure S2. During follow-up, 184 new patients (13.9%) presented abnormal values of blood pressure meeting hypertension criteria, 136 (10.3%) showed LDL cholesterol over 115 mg/dL, and 130 (9.8%) glycaemic values or HbA1c determinations within the diabetic range.

Figure 1

Proportion (percentage) of patients with poor control of each major CV risk factor according to the objectives included in the ESC guidelines, both at baseline and at each visit during follow-up. The Y-axis refer to the percentage (%) of patients outside of the recommended ranges for each CV risk factor. The X-axis illustrate the months elapsed since the baseline visit.

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Relationship with CTox

Individual risk factors at baseline were not related with an increased risk of severe CTox during follow-up. Furthermore, hypercholesterolaemia was found to be related with a borderline lower incidence of in severe CTox incidence: OR for hypertension was 0.77 [95% confidence interval (CI) 0.31–1.92], OR for diabetes mellitus was 1.36 (0.51–3.63), OR for hypercholesterolaemia was 0.45 (0.21–0.97), and OR for tobacco use was 1.4 (0.52–3.75). Moreover, the number of risk factors presented by an individual patient at baseline was not related with the development of severe CTox either: OR for one risk factor was 0.51 (0.22–1.16), OR for two risk factors was 1.47 (0.64–3.39), and OR for ≥3 risk factors was 0.53 (0.71–3.95). However, a positive trend relationship was found between CV risk SCORE index and severe CTox (P for linear trend 0.045) (Figure 2, Supplementary material online, Table S3).

Figure 2

Proportion (percentage) of patients who developed cardiotoxicity (CTox) or all-cause mortality during follow-up according to the SCORE category: low to intermediate risk or SCORE <5%, high risk or SCORE 5–10%, and very high risk or SCORE ≥10%.

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Relationship with all-cause mortality

A total of 112 patients died during follow-up. The majority of these deaths were due to cancer, and only 14 patients (12.5%) died due to CV causes. None of the individual CV risk factors at baseline was associated with a higher mortality. On the other hand, hypercholesterolaemia was related with a small benefit in mortality during follow-up. Detailed data are shown in Supplementary material online, Table S3, whereas the Kaplan–Meier curves for all-cause mortality are depicted in the Supplementary material online, Figure S3, comparing smokers vs. non-smokers (HR 1.01; 95% CI 0.57–1.80), hypertensive vs. normotensive patients (HR 1.30; 95% CI 0.86–1.95), diabetics vs. non-diabetics (HR 1.33; 95% CI 0.77–2.29), and patients with high and normal LDL cholesterol values (HR 0.66; 95% CI 0.46–0.97). The number of risk factors also failed to demonstrate a relationship with long-term mortality (Supplementary material online, Figure S4). However, higher SCORE index categories clearly showed an incremental risk for all-cause mortality during follow-up, with HR 1.79 (95% CI 1.16–2.76) for SCORE 5–9 and HR 4.90 (95% CI 2.44–9.82) for SCORE ≥10 when compared with patients with lower SCORE (0–4) (Figures 2 and 3).

Figure 3

Kaplan–Meier survival analysis with the log-rank test stratified according to the SCORE category: low to intermediate risk or SCORE <5%, high risk or SCORE 5–10%, and very high risk or SCORE ≥10%.

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Discussion

The relationship between cancer and CV risk factors remains controversial and a subject of intense debate and research.^12,13 Even though CV risk factors remain key determinants of prognosis in the global population,^1–3,10,14 data regarding its potential impact or interaction in patients receiving cardiotoxic treatments for cancer are scarce.^15–17 Current recommendations and position papers from the cardio-oncology community^4,5,18,19 emphasize the relevance of medical therapy and lifestyle recommendations focused on achieving optimal CV risk control. Nevertheless, high-quality evidence that support these recommendations is lacking, and information regarding the actual usefulness of CV risk factor assessment in the prognostic evaluation of cancer patients remains largely unknown.

Prevalence of risk factors in cancer patients

Our prospective, multicentre registry including a large cohort of patients treated with potentially cardiotoxic drugs showed a significant prevalence of pre-existent CV risk factors, particularly considering that most participants were relatively young and predominantly female. Moreover, baseline evaluation before oncological treatment significantly improved the rate of CV risk factor diagnosis. A comparison between our cohort and contemporary data from large population-based studies and primary care registries in Spain^20–22 showed higher prevalence of diabetes and hypercholesterolaemia and lower rates of hypertension and tobacco use, although direct comparison between these studies remains difficult, given the different methodologies and patients included.

CV risk factors during follow-up

Virtually no prior studies have explored the evolution of CV risk factors during active chemotherapy. In our study, a dedicated cardio-oncology clinic proved to be useful in the detection of new diagnosis of hypertension, diabetes, and hypercholesterolaemia in 13.9%, 9.8%, and 10.3% of patients, respectively during follow-up. Blood pressure control slightly improved during the first 6 months of treatment, while the proportion of patients with glycaemic and lipid values within guideline-directed objectives decreased, the later despite clinical surveillance performed by physicians with specific dedication to cardio-oncology and primary/secondary prevention. Potential causes include adverse effects of oncological treatment,²³ lack of compliance from patients or other clinical providers,⁸ and cancer-related effects.¹² However, the finding of poor CV risk control in a selected group of patients subjected to theoretically strict CV monitorization is no unique or novel. Two large cross-sectional studies undertaken at 78 and 131 centres across all Europe,^24,25 focused on secondary prevention and risk factor control among coronary patients, showed that the majority of patients do not achieve guideline standards for secondary prevention despite high reported use of CV medications. Therefore, the development of modern and multidisciplinary strategies to improve patient adherence to risk factor treatment and healthier lifestyles remains an urgent and unmet need. Specifically, supervised exercise rehabilitation programmes may play a key role in this group of patients.^26,27

CV risk factors and CTox

We were not able to find a significant relationship between individual major CV risk factors or their combination before the initiation of potentially cardiotoxic treatments and the development of severe CTox or all-cause mortality during follow-up. Most evidence regarding the association between CV risk factors, cancer, and long-term survival comes from retrospective community-based studies or cohort studies including survivors of childhood cancer.^28–31 Not only these investigations reported a higher prevalence of CV risk factor among cancer survivors when compared with the general population, but also found increased CV events during follow-up in cancer patients with major CV risk factors. A possible explanation may be that this research has typically focused on very long-term outcomes, whereas our analysis reports on the 2-year period immediately after the initiation of chemotherapy. The pathobiology of CV risk factors in the context of cardiotoxic treatment remains largely undefined, but their negative consequences may have a longer latency period.

Interestingly, hypercholesterolaemia was associated with a small survival benefit during follow-up. Hypercholesterolaemia has been inconclusively linked to several types of cancer, specially breast cancer,^12,32 and its control has been recommended by expert consensus due to its known relationship with coronary artery disease and its perceived potential to increase the risk of cardiac events in cancer patients.³³ Nevertheless, convincing evidence supporting the role of hypercholesterolaemia in the development of CTox is lacking. Ongoing research focuses on the potential benefit of statin therapy to decrease the incidence of CV events among anthracycline-treated patients, due to its anti-inflammatory and antioxidant effects.^34,35 However, statin treatment at baseline or its initiation during the study period was not associated with a survival benefit in our cohort of oncological patients receiving potentially cardiotoxic drugs. Thus, the mechanism linking hypercholesterolaemia and a better survival in our study is uncertain and may be an equivocal finding in a non-specific registry. Even though it could be a random-related effect, another possible explanation may be the so-called risk factor paradox in wasting diseases,^36,37 for which the characteristics of survivors in these types of conditions may be in clear contradiction with those predicted by traditional risk factors.

SCORE risk and outcomes

A major finding in the present study was the observation of a significant relationship between higher SCORE risk and severe CTox and all-cause mortality during a 2-year follow-up after the initiation of potentially cardiotoxic treatment. The European guidelines on CV disease prevention^1,10 recommend the use of SCORE to assess the risk of fatal and total CV disease, and its use has been suggested in cancer patients as part of the preliminary work-up before the initiation of chemotherapy.³⁸ However, evidence regarding the usefulness of CV risk scores in the oncological population is scarce and a small, retrospective study including HER-2 positive breast cancer patients showed that the Framingham Risk Score underestimated the risk of CV events during follow-up.³⁹ To the best of our knowledge, this is the first study showing a relationship between higher SCORE and all-cause mortality in patients treated with potentially cardiotoxic drugs. Even though this finding should be taken with caution, it highlights the importance of CV risk assessment and opens the door for its use in patients with cancer treated with high-risk chemotherapy in order to easily identify patients that need a closer follow-up during treatment.

Limitations

The strengths of this study include the prospective collection of a broad range of commonly used clinical, biomarker, and echocardiographic data at pre-specified frequent intervals during a 2-year follow-up in patients with different forms of cancer receiving treatments previously related with a relatively high incidence of CTox. A number of missing visits or incomplete data collection during follow-up represents a limitation to accurately estimate the prevalence of CV risk factors during follow-up as well as its relationship with outcomes but was unavoidable due to priorities in the treatment of cancer patients. Similarly, treatments received by patients during follow-up (specifically an increase in CV drug prescription at a patient level) and compliance with the medical recommendations could not be ascertain with precision due to the nature of the registry.

The main objective of the present paper was to describe the prevalence, incidence and individual CV risk factor influence in cancer patients receiving cardiotoxic drugs. Therefore, the finding of higher SCORE assessment linked to all-cause mortality should be confirmed with the development of predictive and explanatory multivariate models to rule out potential confounders. Future research should focus on the development of a specific prospective scoring system assessing CV and CTox risk in cancer patients. This will further help defining the true relationship between major CV risk factors and the development of CV events after the initiation of chemotherapy. Furthermore, whether aggressive treatment of these CV risk factors improves patient prognosis and the potential benefits of achieving widely recognized therapeutic goals recommended in international prevention guidelines should also be explored.

Conclusions

This relatively young large cohort of patients treated with a potentially cardiotoxic regimen showed a significant prevalence of CV risk factors. Furthermore, this prevalence increased during follow-up and diabetes and lipid control worsened during chemotherapy treatment in spite of strict management in a dedicated cardio-oncology clinic. Baseline CV risk assessment using SCORE predicted severe CTox and all-cause mortality during follow-up and its use should be recommended in the evaluation of all cancer patients.

Supplementary material

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

Funding

This study was partially funded by the Fondo Investigaciones Sanitarias, Spain (FIS 113/00559), Centro de Investigación Biomédica en Red Cardiovascular CIBER-CV (Spain), and Instituto de Investigación Hospital Universitario La Paz (IdiPaz).

Conflict of interest: J.L.S. reports grants from Novartis, Bayer, Merk, DalCore, and Sanofi; personal fees from Menarini and Servier, outside the submitted work. M.C.A. reports personal fees from Celgene, Janssen, Roche, Sandoz, Servier, Takeda, Novartis, Gilead, Amgen, and Karyopharm, outside the submitted work. J.F.B. reports personal fees from Amgen, Ipsen, Eissai, Merk, Roche, and Novartis, outside the submitted work. O.R.F. reports grants from Fundación Jose Luis Castaño-Spanish Society of Laboratory Medicine, outside the submitted work. T.L.F. reports personal fees from Janssen, Gilead, Pfizer, Novartis, Daiichi Sankyo, and TEVA, outside the submitted work. All other authors have nothing to disclose.

References

APPENDIX

List of CARDIOTOX registry investigators

La Paz University Hospital, IdiPaz, UAM, Madrid

Executive Committee

José López Sendón (1) (Chairman)

Antonio Buño Soto (4)

Miguel Canales Albendea (5)

Enrique Espinosa (3)

Jaime Feliu Batlle (3)

Teresa López-Fernández (1)

Esteban López de Sá (1)

Mar Moreno Yangüela (1)

Elena Ramírez (2)

Olaia Rodríguez Fraga (4)

(1) Servicio de Cardiología

(2) Servicio de Farmacología Clínica

(3) Servicio de Oncología Médica

(4) Servicio de Análisis Clínicos

(5) Servicio de Hematología

(6) Fundación para la Investigación Biomédica del Hospital Universitario La Paz

Investigators

La Paz University Hospital, IdiPaz, UAM

Cardiology

Ainara Albaladejo

Guiomar Mediavilla

Carlos Álvarez-Ortega

Teresa López-Fernández

José López-Sendón

Mar Moreno Yangüela

Silvia Valbuena

Regina Dalmau

Almudena Castro

Esteban López de Sá

Juan Caro Codón

Oncology

Pilar Zamora Auñon

Jaime Feliu Batlle

Enrique Espinosa

Beatriz Castelo

Andrés Redondo

Álvaro Pinto

HematoOncology

Miguel Canales Albendea

Pilar Gómez Prieto

Central Laboratory

Antonio Buño Soto

Patricia Chanca

Paloma Oliver

Olaia Rodríguez Fraga

Oncoradiotherapy

Isabel Rodríguez

Lara Miralles

Belén Belinchón

Aurea Manso

Rosa Moreiras

Pharmacy

Gema Casado

Alicia Herrero

Hospital Universitario de Bellvitge, IDIBELL, L’Hospitalet de Llobregat, Barcelona

José González-Costello

Sonia Pernas Simón

Hospital Clínico Santiago de Compostela

José Ramón González-Juanatey

Pilar Mazón Ramos

Amparo Martínez Monzonis

Rafael López López

Patricia Palacios Ozores

Milagros Pedreira Pérez

Belén Álvarez Álvarez

Hospital Lucus Augusti, Lugo

Begoña Campos Balea

Carlos González-Juanatey

Ana Testa Fernández

Silvia Varela Ferreiro

Hospital de Fuenlabrada, Madrid

José María Serrano Antolín

Juan Antonio Guerra Martínez

Luis Javier Morales García

Carlos Gutierrez Landaluce

Elena Moreno Merino

Nieves Estival Ortega

Hospital de Getafe, Madrid

Joaquin Alonso

Hospital General Universitario Gregorio Marañón

Francisco Fernández Avilés

Ana González-Mansilla

Pilar García Alfonso

Servicio de Cardiología, Hospital Infanta Sofía, Madrid

Rosalía Cadenas Chamorro

María Merino Salvador

Ignacio Plaza

Hospital San Juan, Alicante

Vicente Bertomeu

Juan Quiles

Author notes