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Kardiologia Polska 2015; 73, 9: ; DOI: /KP.a ISSN ARTYKUŁ ORYGINALNY / ORIGINAL ARTICLE Assessment of risk factors for mortality in patients with cardiovascular disease
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Kardiologia Polska 2015; 73, 9: ; DOI: /KP.a ISSN ARTYKUŁ ORYGINALNY / ORIGINAL ARTICLE Assessment of risk factors for mortality in patients with cardiovascular disease and a history of treatment for malignancy Jarosław Rydzek 1, 2, Zbigniew T. Gąsior 3, Józefa Dąbek 3, Jerzy Wojnar 4, Michał Skrzypek 5 1 Świętokrzyskie Centre of Cardiology, Kielce, Poland 2 Voivodship Polyclinical Hospital, Czestochowa, Poland 3 Department of Cardiology, SHS, Medical University of Silesia, Katowice, Poland 4 Department of Internal Medicine and Oncologic Chemotherapy, SMK, Medical University of Silesia, Katowice, Poland 5 Department of Biostatistics, SPDLM, Medical University of Silesia, Katowice, Poland Abstract Background: Patients with advanced cancer after radio- and/or chemotherapy are increasingly commonly hospitalised in cardiology units due to coexisting cardiovascular diseases (CVD). A rational assessment of mortality risk is an important part of patient preparation for invasive cardiac procedures. One disadvantage of cardiac risk scores is the fact that malignancies are not taken into account. At present, accurate estimation of life expectancy is possible in up to 20% of patients with an advanced malignancy. Aim: To evaluate the effect of selected clinical parameters on survival of patients with CVD and coexisting lung or breast cancer after radio- and/or chemotherapy. An additional aim was to identify patients with a high probability of surviving a year in a good general clinical condition. Methods: The study group involved 326 subjects with established CVD and lung cancer (small-cell or non-small-cell) or breast cancer who were selected from the group of 7818 patients receiving palliative care in the Palium hospice in Czestochowa, Poland, in The obtained data were collected in a database and subjected to a statistical analysis. Results: The strongest factors associated with an increased risk of death among patients with CVD and coexisting advanced lung or breast cancer after chemo- and/or radiotherapy were the type and stage of malignancy, functional status according to the ECOG classification, and the presence of cachexia. Other factors that had a significant effect on survival included higher severity of heart failure symptoms as evaluated by the New York Heart Association class, decreased left ventricular ejection fraction, presence of ischaemic heart disease, chronic obstructive pulmonary disease, fasting hyperglycaemia, and the severity of fatigue, nausea, and pain. When the effects of drug treatment on survival were analysed, significantly increased survival was observed in patients treated with angiotensin-converting enzyme inhibitors while diuretic and glucocorticosteroid use was associated with decreased survival. Among the evaluated groups of patients with CVD and advanced malignancy after radio- and/or chemotherapy, the highest probability of surviving a year in a relatively good general clinical condition was noted in patients with stage 3 breast cancer without cachexia, ischaemic heart disease and persistent somatic symptoms who were treated with tamoxifen, angiotensin-converting enzyme inhibitors and megestrol acetate. Conclusions: This is the first study that evaluated the combined effect of oncological and cardiovascular risk factors on survival of patients with CVD and coexisting cancer after radio- and/or chemotherapy treatment. When the three groups of cancer patients with different prognosis were compared, the study revealed varying effects of each factor depending on the underlying malignancy. The analysis confirmed the significance of the cumulative risk. The present study showed that malignancy-related prognostic factors are important in the context of cardiac evaluation and treatment of cancer patients. It also showed that further research is needed to clarify these issues. Key words: malignancy, cardiovascular diseases, prognosis, therapy Kardiol Pol 2015; 73, 9: Address for correspondence: Prof. Zbigniew T. Gąsior, Department of Cardiology, SHS, Medical University of Silesia, ul. Ziołowa 45, Katowice, Poland, Received: Accepted: Available as AoP: Copyright Polskie Towarzystwo Kardiologiczne Assessment of risk factors for mortality in patients with CVD and a history of treatment for malignancy INTRODUCTION Patients with an advanced cancer after oncologic treatment are increasingly commonly hospitalised in cardiology units due to coexisting cardiovascular diseases (CVD). Thus, there is an increasing need for various invasive procedures, and patient selection for invasive treatment becomes more complex. A rational assessment of mortality risk is an important part of patient preparation for invasive cardiac procedures. This is particularly important in case of procedures that lead to long-term prognostic benefits. Life expectancy over 1 year is an important factor when choosing the type of cardiac resynchronisation therapy device and implanting a cardioverter-defibrillator. As indicated by the guidelines, it is also of major importance when selecting patient for surgical myocardial revascularisation or transcutaneous aortic valve implantation. It is also among major factors to be considered when contemplating fibrinolytic therapy for acute proximal deep vein thrombosis, and making decisions regarding angioplasty and stenting. In current cardiology practice, mortality risk scores have become an essential component of patient selection for invasive procedures. The most commonly used cardiac risk scores include GRACE, SEATTLE, EuroSCORE, and STS. However, these commonly used clinical tools do not include malignancy and oncologic treatment in the diagnostic and therapeutic process, leading to an increased debate among experts regarding limitations of the currently used risk scores and the rationale for their improvement and update [1]. Estimation of 1-year survival is most challenging in patients with an advanced malignancy. At about 1 year before dying, a patient with malignancy is usually in a better condition than a patient with diabetes, previous stroke, chronic heart failure, or chronic obstructive pulmonary disease (COPD), while during the terminal month of life, the functional status of a patient with malignancy is usually worse compared to patients with other chronic disease [2]. Patients with an advanced malignancy are at an increased risk of adverse cardiovascular (CV) outcomes, but their short life expectancy often precludes invasive cardiac treatment. In clinical practice, it is important to answer the question whether specific therapy will bring objective benefits including prolongation of life and improvement of the quality of life. At present, accurate estimation of life expectancy is possible in up to 20% of patients with an advanced malignancy [3 5]. Studies indicate that patients with an advanced malignancy may be, sometimes incorrectly, denied optimal cardiac therapy based on underestimated prognostic factors. On the other hand, use of too invasive diagnostic and therapeutic procedures, often contributing to patient discomfort, may be not justified from the ethical point of view. Careful evaluation of prognostic factors in patients with an advanced malignancy treated with radio- and/or chemotherapy and concomitant CVD may result in better therapeutic and diagnostic decision. The main aim of the study was to evaluate the effect of selected clinical parameters on survival of patients with CVD and coexisting lung or breast cancer treated with radio- and/or chemotherapy. An additional aim was to identify patients with a high probability of surviving a year in a good general clinical condition. METHODS Study group We studied 326 patients with established CVD and breast or lung cancer (small cell or non-small cell) treated with radioand/or chemotherapy who were selected from the group of 7818 patients receiving palliative care in the Palium hospice in Czestochowa, Poland, in The patients were divided into three groups depending on the underlying malignancy: breast cancer (BC 99 patients), non-small cell lung cancer (NSCLC 196 patients), and small cell lung cancer (SCLC 31 patients). Study plan This prospective case-control study included evaluation of survival in the study group in relation to: the type of malignancy and its severity; concomitant CVD including ischaemic heart disease (IHD), hypertension, atrial fibrillation, and the severity of heart failure symptoms as evaluated using the New York Heart Association (NYHA) classification; other common concomitant diseases: COPD, diabetes, and fasting hyperglycaemia; selected prognostic factors of an established value in malignancies: functional status evaluated using the Eastern Cooperative Oncology Group (ECOG) scale, somatic factors such as severity of dyspnoea, pain evaluated using the visual analogue scale, severity of nausea, fatigue evaluated using the Likert scale, and the presence of cachexia; selected prognostic factors of an established value in CVD: resting heart rate and left ventricular ejection fraction (LVEF); drug treatment used, including angiotensin-converting enzyme inhibitors (ACEI), beta-blockers, megestrol acetate, diuretics, and dexamethasone in all three patient groups, and tamoxifen in patients with BC. The study protocol included: detailed history; physical examination; blood pressure and heart rate measurements according to the European Society of Hypertension guidelines; fasting capillary blood glucose level measurements using the Accu-Chek Active glucose meter (device precision in accordance with the DIN EN ISO 15197:2003 standard). 731 Jarosław Rydzek et al. Patients were evaluated three times: at baseline, after 3 weeks, and within 7 days before death. Statistical analysis Statistical analyses were performed using the SAS package, version 9.2 (SAS Institute Inc., Gary, NC), with the level of statistical significance at a = Normal distribution of quantitative variables was verified using the Shapiro-Wilk test. Parameters of quantitative variable distribution were compared using the Student t test for normally distributed variables and the Mann-Whitney U test for non-normally distributed variables with categorisation to two groups, and analysis of variance for normally distributed variables and the Kruskal-Wallis test for non-normally distributed variables with categorisation to more than two groups. Univariate survival analysis was performed using the Kaplan-Meier approach for qualitative descriptors and the Cox regression model for quantitative descriptors. Multivariate analysis was used to summarise simple univariate analysis using the Cox survival analysis with non-proportional hazard function, as the rule of proportional hazards, a prerequisite for the proportional hazard Cox model, was violated. Calculations were performed using a macro prepared for the SAS program. Multivariate model included variables with p 0.02 in univariate analyses, with their stepwise elimination until only significant (p 0.05) variables remained in the model. To evaluate the effect of the evaluated factors on the likelihood of surviving at least 1 year, univariate logistic regression analysis was used and receiver operating characteristic curves were plotted. RESULTS Study group characteristics We studied 326 patients aged 42 to 89 years. The mean age of women did not differ significant from that of men (67.1 vs years; p = 0.36). No age differences were also noted between patients with various malignancies. Tables below show basic characteristics of the study group of patients with a malignancy and concomitant CVD, including dichotomous variables (Table 1), ordinal variables (Table 2), and quantitative variables (Table 3). The median survival from the diagnosis of a malignancy was 96, 12, and 4.8 months in patients with BC, NSCLC and SCLC, respectively (p 0.01). Patient survival in relation to the type of malignancy is shown in Figure 1. The median survival from admission to the hospice was 2.5, 1.6, and 1.2 in patients with BC, NSCLC and SCLC, respectively (p 0.01). Patient survival from admission to the hospice in relation to the type of malignancy is shown in Figure 2. Multivariate analysis of parameters associated with survival in patients with BC and concomitant CVD, with corresponding relative hazard values, is shown in Figure 3. Table 1. Characteristics of the study group including demographic data, type of malignancy, concomitant conditions, and drug treatment used Age [years] Gender: 67.8 ± 10 (42 89 years) Women 150 (46%) Men 176 (54%) Type of malignancy: Breast cancer 99 (30.5%) Non-small cell lung cancer 196 (60%) Small cell lung cancer 31 (9.5%) Concomitant conditions: Ischaemic heart disease 252 (77.3%) Hypertension 88 (26.9%) Atrial fibrillation 141 (43.2%) Diabetes 20 (6.1%) COPD 153 (47%) Cachexia 214 (65.6%) Medications: ACEI 117 (35.8%) Beta-blocker 72 (22.0%) Tamoxifene 33 (10.1%) Megestrol acetate 156 (47.8%) Diuretic 167 (51.2%) Dexamethasone 162 (49.6%) ACEI angiotensin-converting enzyme inhibitor; COPD chronic obstructive pulmonary disease In patients with BC, variables associated with increased survival included treatment with ACEI, megestrol acetate, and tamoxifen (p 0.01), while only a nonsignificant trend was noted for beta-blocker used compared to non-use. Analysis of survival predictors in patients with NSCLC and CVD is shown in Figure 4. Reduced survival was associated with more advanced malignancy, higher ECOG class, higher severity of somatic complaints, higher NYHA class, presence of IHD, higher resting heart rate, lower LVEF, fasting hyperglycaemia, concomitant COPD, and use of diuretics and dexamethasone. Prognostic factors in patients with SCLC are shown in Figure 5. In patients with SCLC, factors associated with significantly shorter survival included more advanced malignancy, higher ECOG class, higher severity of persisting somatic complaints, higher heart failure severity as evaluated by the NYHA class, presence of IHD, atrial fibrillation, higher resting heart rate, lower LVEF, concomitant COPD, non-use of ACEI, and use of diuretics. In this patient group, treatment with beta-blockers and megestrol acetate was associated with only a trend towards increased survival (p = 0.58). 732 Assessment of risk factors for mortality in patients with CVD and a history of treatment for malignancy Table 2. Basic descriptive statistics for ordinal variables NYHA class Measurement 1 (n = 326) Measurement 2 (n = 228) Measurement 3 (n = 220) I 37 (11.3%) 31 (13.6%) II 62 (19.0%) 43 (18.9%) III 95 (29.1%) 75 (32.9%) 24 (10.9%) IV 132 (40.5%) 79 (34.6%) 196 (89.1%) Blood pressure [mm Hg] Measurement 1 (n = 326) Measurement 2 (n = 232) Measurement 3 (n = 224) Range Mean Median Range Mean Median Range Mean Median Systolic ± ± ± Diastolic ± ± ± ECOG Measurement 1 (n = 326) Measurement 2 (n = 261) Measurement 3 (n = 251) (10.7%) 32 (12.3%) 2 75 (23.0%) 66 (25.3%) 3 87 (26.7%) 63 (24.1%) 52 (20.7%) (39.6%) 100 (38.3%) 199 (79.3%) Severity of fatigue on admission to the hospice [Likert scale] (n = 326) Not present at all 31 (9.5%) Rather not present 50 (15.3%) Marked fatigue 93 (28.5%) Constant fatigue 152 (46.7%) Nausea [Likert scale] (n = 326) 1 98 (30.0%) 2 86 (26.4%) (33.7%) 4 32 (9.8%) ECOG Eastern Cooperative Oncology Group; NYHA New York Heart Association 733 Jarosław Rydzek et al. Table 3. Basic descriptive statistics for quantitative data Parameter (number of observations) Range Mean ± SD Median LVEF [%] (n = 189) ± Fasting glucose [mg/dl] (n = 326) ± Resting heart rate [bpm]: Measurement 1 (n = 326) ± Measurement 2 (n = 229) ± Measurement 3 (n = 219) ± Measurements of LVEF and blood glucose were performed at baseline, and heart rate was measured during each visit. LVEF left ventricular fraction; SD standard deviation Figure 1. Survival from the diagnosis of malignancy with 95% confidence intervals in relation to the type of malignancy; BC breast cancer; NSCLC non-small cell lung cancer; SCLC small cell lung cancer Our analysis of the study group identified factors associated with the highest likelihood of surviving 1 year. These included the diagnosis of stage III BC, no IHD, grade 1 severity of nausea, treatment with tamoxifen, megestrol acetate, and ACEI, and non-use of dexamethasone. DISCUSSION Malignancy and previous oncologic therapy are factors potentially associated with increased 1-year mortality and should be taken into account when selecting patients for invasive CV treatment. Appropriate therapeutic decision must be based on the cumulative risk related not only to the primary CV disorder but also concomitant conditions and symptoms, their treatment, and interactions between these factors. In our study, we compared three groups of patients with different malignancies with varying prognosis and showed different effects of the evaluated factors depending on specific malignancy (Figs. 3 5). Figure 2. Survival from the admission to the hospice in relation to the type of malignancy; BC breast cancer; NSCLC non- -small cell lung cancer; SCLC small cell lung cancer The presence of coronary artery disease had a significant effect on survival in all three groups of patients with an advanced malignancy. Deaths due to myocardial infarction were documented in 6 patients in the study group. Symptomatic coronary artery disease may be a reason for, sometimes incorrect, denial of appropriate oncologic therapy, while previous oncologic therapy may lead to premature coronary artery disease [6]. On the other hand, myocardial revascularisation may be necessary before appropriate oncologic treatment. Higher severity of heart failure as evaluated by the NYHA class significantly increased mortality among patients with an advanced malignancy in our study group. In most patients with a history of malignancy who were hospitalised for cardiac reasons, heart failure resulted from the underlying CVD. Drug treatment of heart failure may rapidly reduce its clinical symptoms and have a beneficial prognostic effect. We found no significant effect of hypertension on survival in the study group. This might have resulted from a relatively short duration of follow-up. 734 Assessment of risk factors for mortality in patients with CVD and a history of treatment for malignancy Figure 3. Hazard ratios (HR) for breast cancer (model including all cases, n = 99); ACEI angiotensin-converting enzyme inhibitor; COPD chronic obstructive pulmonary disease; ECOG Eastern Cooperative Oncology Group; NYHA New York Heart Association; IHD ischaemic heart disease; LVEF left ventricular ejection fraction Figure 4. Hazard ratios (HR) for non-small cell lung cancer (NSCLC) (model including all cases, n = 196); ACEI angiotensin- -converting enzyme inhibitor; COPD chronic obstructive pulmonary disease; ECOG Eastern Cooperative Oncology Group; NYHA New York Heart Association; IHD ischaemic heart disease; LVEF left ventricular ejection fraction 735 Jarosław Rydzek et al. Figure 5. Hazard ratios (HR) for small cell lung cancer (SCLC) (n = 31); ACEI angiotensin-converting enzyme inhibitor; COPD chronic obstructive pulmonary disease; ECOG Eastern Cooperative Oncology Group; NYHA New York Heart Association; IHD ischaemic heart disease; LVEF left ventricular ejection fraction Atrial fibrillation is associated with twice increased mortality regardless of other established factors contributing to mortality [7, 8]. In our analysis, mortality was increased in patients with atrial fibrillation but the difference in BC patients was not significant. In a prognostic study of patients with colon cancer and diabetes reported by Feng et al. [9], reduced 5-year survival was shown in diabetic patients. In our study, a nonsignificant trend was noted for an increased mortality among patients with diabetes in all three study groups. Concomitant COPD had a significant effect on reduced survival in patients with an advanced malignancy. Lung cancer is more common in CO
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