Cancer Antigen 125 is Associated with Length of Stay in Patients with Acute Heart Failure

Patients and Methods

A total of 300 consecutive patients, admitted to the emergency unit and then hospitalized at Cumhurivet University Hospital (Turkey) for decompensated HF from January 2011 through January 2015, were prospectively considered for enrollment in this study. Subsequently excluded from the 300 were 33 patients: 11 patients with previous diagnoses of malignancies, 3 with previous diagnoses of cirrhotic hepatic disease, 5 with diagnoses of active inflammatory diseases, 1 with a diagnosis of nephrotic syndrome, 8 with a high CA-125 level (≥300 U/mL, suspected malignancy), and 5 with diagnoses of gynecologic diseases (Fig. 1). The remaining 267 patients (184 men and 83 women) were enrolled in the study after giving their informed consent. The study was performed in accordance with the Declaration of Helsinki for Human Research, and was approved by our hospital's institutional review board.

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Decompensated HF was diagnosed on the basis of recent deterioration of symptoms in combination with signs of HF, as suggested in published guidelines.^20,21 Blood samples for CA-125 and other routine testing were taken within 30 minutes of admission. The samples were stored under appropriate conditions, then serum CA-125 levels were determined with use of the AxSYM^® Plus Immunoassay Analyzer (Abbott Laboratories; Abbott Park, Ill). The AxSYM CA-125 assay has its basis in microparticle enzyme immunoassay, a technology that uses a solution of suspended, submicron-sized latex particles for the purpose of measurement. Throughout their hospitalizations, all patients were monitored by a cardiologist who was blinded to the study and to the treatment methods; the time of discharge was decided by this cardiologist. Each patient's LOS, chronic HF medications, in-hospital medications—including positive inotropic agents (dopamine, dobutamine, or both)—and other data at admission, were obtained by the same cardiologist. Hypertension was defined as blood pressure ≥140/90 mmHg on more than 2 occasions during official measurements or as the patient's being on antihypertensive therapy. Diabetes mellitus (DM) was defined as a fasting blood glucose level ≥126 mg/dL or as the patient's being on antidiabetic therapy.

Transthoracic echocardiographic examinations were undertaken by experienced echocardiographers, blinded to the study, via the Vivid 7^® cardiac ultrasonography system (GE VingMed Ultrasound AS; Horten, Norway) with 2.5- to 5-MHz probes. The left ventricular ejection fraction (LVEF) was calculated with use of the modified Simpson method, in line with the most recent European Society of Cardiology guidelines.²¹ Chamber sizes were defined in accordance with published guidelines.²² Systolic pulmonary artery pressure (SPAP) was calculated by using the peak velocity of tricuspid regurgitation and an estimate of right atrial pressure.^23,24 The presence or absence of pericardial effusion was noted.

Results

The mean age of the patients was 68 ± 11 years. The median LVEF was 0.37, and there were 144 HF patients with reduced LVEF and 123 HF patients with preserved LVEF. The median CA-125 level was 46 U/mL. The median LOS was 4 days, and the mean LOS was 4.7 ± 3 days (range, 1–15 d).

Patients were classified into 2 groups on the basis of median LOS (LOS ≤4 d versus >4 d). Table I shows the baseline clinical characteristics of the patients in terms of that LOS. Patients with LOS >4 days had higher CA-125 levels than did patients with LOS ≤4 days (114 [range, 9–298] U/mL vs 19 [range, 3–68] U/mL; P<0.001). Moreover, patients with LOS >4 days were older and had larger left atrial diameters, higher SPAP measurements, and higher blood urea nitrogen (BUN) and creatinine levels. In addition, the presence of DM, AF, right ventricular dilation, and pericardial effusion—together with the rate of using positive inotropic drugs—were higher in patients with LOS >4 days. However, LVEFs, blood levels of sodium, potassium, and albumin, and the rates of prehospital use of β-blockers and diuretics were lower in patients with LOS >4 days.

TABLE I. Baseline Characteristics of the Patients

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In HF patients, CA-125 levels correlated positively with age, SPAP, left atrial diameter, and BUN and creatinine levels; they were associated with the presence of DM, AF, right ventricular dilation, and pericardial effusion, and with the use of positive inotropic agents while in the hospital. Conversely, CA-125 was negatively correlated with sodium, potassium, albumin, and hemoglobin levels, and with LVEF; it was associated with the prehospital use of β-blockers and diuretics (Table II).

TABLE II. Spearman Correlation Coefficients for CA-125

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The optimal cutoff level of CA-125 in the prediction of prolonged LOS was found to be >48 U/mL, with specificity of 95.8% and sensitivity of 96% (AUC=0.979; 95% CI, 0.953–0.992; P =0.0001 (Fig. 2).

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Table III shows the results of the univariate and multiple logistic regression analyses of prolonged LOS. A CA-125 level >48 U/mL on admission and many other factors had prognostic significance in univariate analysis, whereas in the multiple logistic regression model, using the forward stepwise method, CA-125 level >48 U/mL (OR=4.562; 95% CI, 1.826–11.398; P=0.001), sodium level (OR=0.727; 95% CI, 0.655–0.807; P <0.001), creatinine level (OR=2.004; 95% CI, 1.193–3.367; P=0.009) and the presence of AF (OR=2.073; 95% CI, 1.149–3.74; P=0.015) remained associated with an increased risk of prolonged LOS, after adjusting for the variables found to be statistically significant in the univariate analysis and for the variables correlated with the CA-125 level.

TABLE III. Univariate and Multivariate Analyses for Prolonged Length of Stay

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Discussion

To our knowledge, for the first time in the medical literature, we have illustrated that high CA-125 levels are independently associated with prolonged LOS in patients hospitalized with acute decompensated HF. This decompensation has an increased prevalence in developed countries because of the higher average ages there; and the prolonged and frequent hospitalizations create a severe financial burden.^25–29 In addition, prolonged hospitalization leads to hyponatremia, hypoalbuminemia, hypokalemia, renal and hepatic insufficiency, anemia, embolic and hemorrhagic sequelae, and increased nosocomial infections—further increasing morbidity and mortality rates in patients with HF.^30–35

Together with identifying patients who are expected to have prolonged hospitalizations, we need to develop new strategies for the follow-up and treatment of these patients, which would create both economic and clinical advantages. Although limited in number, there are studies that relate to the predictors of LOS in HF patients. One such study³⁶ associated chronic renal failure, COPD, and DM with LOS. Another³⁷ grouped patients in accordance with economic status and evaluated LOS predictors: in multivariate analysis, chronic renal failure was associated with LOS in all economic groups. Whellan and colleagues' study²⁷ of 70,000 patients found that factors such as AF, COPD, DM, chronic renal failure, female sex, low systolic blood pressure, high heart rate, and low levels of hemoglobin, high levels of BUN, and high levels of brain natriuretic peptide were associated with prolonged LOS. Sahin and associates³⁸ found that low systolic blood pressure, high BUN, anemia, and severe mitral insufficiency at the time of admission were independently associated with LOS. In patients older than age 65 years, only female sex and poor functional class at the time of hospitalization were found to be correlated with LOS.³⁹ Finally, low sodium and albumin values at the time of hospital admission and history of hypertension were independently associated with hospitalization longer than 10 days.⁴⁰

As did the previous studies, our current study found that presence of AF and higher creatinine levels were independently associated with hospitalization longer than 4 days. In addition, we found that high CA-125 levels and low sodium levels were associated with prolonged LOS. Although other studies have identified female sex, DM, anemia, and lower albumin levels to be independent predictors, these factors were significant only in the univariate analysis in our study, not in the multivariate analysis. Distinctive from the other investigators of this topic, we evaluated the effects upon LOS of pre-hospital use of oral diuretics and β-blockers for HF and of in-hospital use of positive inotropic agents: the absence of prehospital diuretics and β-blockers and the presence of in-hospital inotropic use were found to be significant for LOS in univariate analysis, but the use of these agents was not independently associated with LOS in multivariate analysis. The prolongation of hospitalization through the use of positive inotropic agents is an expected result, yet prolonged hospitalization in the absence of β-blockers and diuretics could arise from poor clinical conditions or poor prognosis.

Recent studies^12,14–16 have shown that CA-125, long useful as a tumor marker, has prognostic importance in many cardiovascular diseases, especially HF. In studies related to HF, CA-125 values correlated with pulmonary artery pressure, pulmonary artery capillary wedge pressure, left atrial volume index, LVEF, brain natriuretic peptide values, New York Heart Association functional class, and pericardial effusion.^14,15,17 In our study, CA-125 values correlated with SPAP, LVEF, and pericardial effusion.

Basically, the prognostic importance of CA-125 in the pathophysiology of HF can be explained by 2 mechanisms. First, the mechanical stress on mesoendothelial cells, which is produced by increased congestion, leads to CA-125 release from these cells. Second, the neurohormonal effect that develops in HF activates the sympathetic nervous system and the renin-angiotensin-aldosterone system, thus increasing cytokine release and stimulating the inflammatory process—thereby changing the morphology and cell membrane stability of mesoendothelial cells and causing CA-125 release.^35,41,42 According to this sequence, higher CA-125 levels and longer LOS in patients—with high volume loads and increased neurohormonal activation—is the logical result.

Study results show that AF increases left ventricular filling pressures and further impairs systolic and diastolic function in HF patients, thereby increasing mortality rates, stimulating inflammatory activity, and increasing the levels of some cytokines and of CA-125. It is not surprising, therefore, to find that AF, in the current study, is an independent predictor for prolonged hospitalization in patients with HF.^{14,17,19,43,44} In addition to high CA-125 levels and the presence of AF, lower sodium levels and higher creatinine levels are associated with prolonged LOS. This result, consistent with previous studies, is not surprising. It can be claimed that patients who have lower sodium levels and higher creatinine levels are more hypervolemic and produce less urine, because of diuretic resistance.