RU2847170C1 - Method for prediction of probability of hospitalization for heart failure in patients with senile asthenia syndrome aged 80 years and older - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, specifically to cardiology, and can be used to predict the probability of hospitalization or re-hospitalization for decompensation of chronic heart failure for 12 months in patients with senile asthenia syndrome aged 80 years and older. Blood plasma sST2 concentration is determined. If the sST2 concentration exceeds 55.6 ng/ml, a probability of hospitalization is predicted or re-hospitalization for decompensated chronic heart failure for 12 months.

EFFECT: method enables predicting the probability of hospitalization or rehospitalization for decompensated chronic heart failure within 12 months due to the determination of the sST2 biomarker in blood plasma in patients with senile asthenia syndrome aged 80 years and older.

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Description

The invention relates to medicine, namely to cardiology, and can be used to predict the likelihood of developing cardiovascular events, namely hospitalizations, rehospitalizations due to decompensation of chronic heart failure (CHF) within 12 months after determining the sST2 biomarker, ng/ml in blood plasma in patients with frailty syndrome aged 80 years and older.

In the Russian Federation, as throughout the world, there is a progressive aging of the population, one of the characteristic features of which is the growth of the population of people over 80 years old. According to WHO forecasts, by 2025 the number of elderly people will exceed one billion people, which will amount to 15% of the world's population. However, an increase in life expectancy of patients does not mean a preservation of quality of life: older people are more often diagnosed with comorbid pathology (see Golovanova E.D. Patients with polymorbidity and senile asthenia - features of drug therapy. Clinical gerontology. 2019; 25 (7-8): 39-43. DOI: 10.26347/1607-2499201907-08039-043).

Worldwide, special attention is paid to cardiovascular pathology as the main cause of death. Today, more than 80% of elderly people in the population have a history of CHF, which is the main reason for hospitalization of people over 65 years of age (see Kotovskaya Yu.V., Rozanov A.V., Kurashev D.Kh., Tkacheva O.N. Heart failure and frailty syndrome. Medical Council. 2018; 16: 72-79. DOI: 10.21518/2079-701X-2018-16-72-79). The presence of CHF in elderly patients significantly worsens the prognosis, increasing mortality by 33-35% per year (see Orlova Ya.A., Tkacheva O.N., Arutyunov G.P., Kotovskaya Yu.V., Vasuk Yu.A., Lopatin Yu.M., Mareev V.Yu., Mareev Yu.V., Strazhesko I.D., Skvortsov A.A., Runikhina N.K., Frolova E.V. Features of diagnosis and treatment of chronic heart failure in elderly and senile patients. Opinion of experts of the Society of Heart Failure Specialists, the Russian Association of Gerontologists and Geriatricians and the Eurasian Association of Therapists. Cardiology. 2018; 58 (12S): 42-72. DOI: 10.18087/cardio.2560).

According to the EPOCHA study, among all patients hospitalized with cardiovascular diseases (CVD), CHF was the cause of hospitalization in 16.8% of cases (see Mareev, V.Yu. Comparative characteristics of patients with CHF depending on the value of EF according to the results of the Russian multicenter study EPOCHA-O-CHF / V.Yu. Mareev, M.O. Danielyan, Yu.N. Belenkov; on behalf of the working group of the EPOCHA-O-CHF study. // Journal of Heart Failure. - 2006. - Vol. 7, No. 4. - P. 164-171). Almost every second patient in the cardiology department is hospitalized due to decompensation of CHF (see The EuroHeart Failure survey program a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis / J.G. Cleland, K. Swedberg, F. Follath [et al.] // Eur Heart J. - 2003. - Vol. 24 (5). - P. 442-463).

There is a large amount of data on the relationship between the number of hospitalizations and prognosis in patients with CHF. It is known that rehospitalization to a hospital or rehospitalization is considered a risk factor for death and worsening of the course of CHF (see Acute decompensated heart failure. Consensus position of Russian experts - 2014 / V.Yu. Mareev, G.P. Arutyunov, E.I. Astashkin [et al.] // Journal of Heart Failure. - 2014. - Vol. 15, No. 5. - P. 321-336). According to the ESC-HF Pilot study, the rehospitalization rate within one year was 43.9% of cases among patients included in the study after hospitalization and 31.9% of cases among patients included as outpatients (see EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot) / A.P. Maggioni, U. Dahlstrom, G. Filippatos [et al.] // Eur J Heart Fail. - 2013. - Vol. 15 (7). - P. 808-817). It was noted that the risk of death in patients hospitalized repeatedly increased by 1.35 times over 3.6 years compared to the sample of stable patients (see Epidemiological program EPOCHA-CHF: Decompensation of chronic heart failure in real clinical practice (EPOCHA-DCHF) / D.S. Polyakov, I.V. Fomin, F.Yu. Valikulova [et al.] // Journal of Heart Failure. - 2016. - Vol. 17, No. 5 (98). - P. 256-264). Thus, according to a study conducted in the UK, a worsening of survival is reported in patients with De Novo CHF in the presence of hospitalization compared to patients who were not hospitalized and who were diagnosed on an outpatient basis (see Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population-based cohort study / C.J. Taylor, J.M. Ordonez-Mena, A.K. Roalfe [et al.] // BMJ. - 2019. - Vol. 364. - P. 1223).

In addition, the incidence of frailty syndrome (FSS) increases with age, especially in people over 80 years of age. The prevalence of FSS reaches 16% among people aged 80–84 years and 26% in those aged ≥85 years and older (see Kojima G. Prevalence of Frailty in Nursing Homes: A Systematic Review and Meta-Analysis. J. Am. Med. Dir. Assoc. 2015; 16 (11): 940–945. DOI: 10.1016/j. jamda.2015.06.025). The onset and progression of FSS increases the risk of developing dependency on outside care and worsens the prognosis of patients. It has been established that the incidence of SCA development increases in the presence of CHF in patients, which is an independent predictor of emergency conditions in cardiology (see Shlyakhto E.V., Arutyunov G.P., Belenkov Yu.N. National guidelines for determining the risk and preventing sudden cardiac death. 2nd ed. Moscow: 2018. 247 p.).

Currently, determination of the level of natriuretic peptides (NUP) is included in the diagnostic algorithms for CHF and is a necessary research method for making a diagnosis (see Chronic heart failure. Clinical guidelines 2020. Russian Journal of Cardiology. 2020; 25 (11): 4083. doi: 10.15829/1560-4071-2020-4083, Medvedeva E.A., Surkova E.A., Limareva L.V. et al. Molecular biomarkers in diagnostics, risk stratification and prognosis of chronic heart failure. Russian Journal of Cardiology. 2016; (8): 86-91. doi: 10.15829/1560-4071-2016-8-86-91). However, the content of this marker is variable and depends on gender, patient age, the presence of kidney disease, and some infectious diseases. In this regard, the search for new biomarkers of CHF that can mitigate the shortcomings of such laboratory markers of HF seems relevant (see McDonagh TA, Metra M, Adamo M et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 2021; 42 (36): 3599 - 726. doi: 10.1093/eurheartj/ehab368).

Stimulating growth factor ST2 (sST2) is a member of the Toll-like receptor family of interleukin (IL)-1 and has two isoforms: the transmembrane form ST2L, which binds to IL-33 and forms the IL-33/ST2L complex, which has a cardioprotective effect and inhibits myocardial hypertrophy, preventing myocardial fibrosis. The soluble form, however, has opposite effects: it leads to myocardial hypertrophy and fibrosis, dilation of cardiac chambers, and decreased contractility of the left ventricular (LV) muscle. sST2, unlike NT-proBNP, is not affected by age, body mass index (BMI), renal function, or the etiology of HF (see Bayes-Genis, A.; Zamora, E.; de Antonio, M.; Galan, A.; Vila, J.; Urrutia, A.; Diez, C; Coll, R.; Altimir, S.; Lupon, J. Soluble ST2 serum concentration and renal function in heart failure. J. Card. Fail. 2013, 19, 768-775. [CrossRef]). Furthermore, measuring ST2 at the time of admission of a patient with acute HF has been shown to be superior to NT-proBNP in predicting mortality at one year (see Manzano-Fernandez, S.; Mueller, T.; Pascual-Figal, D.; Truong, Q.A.; Januzzi, J.L. Usefulness of soluble concentrations of interleukin family member ST2 as a predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am. J. Cardiol. 2011, 107, 259-267. [CrossRef] [PubMed]).

sST2 is a clinically significant biomarker that reflects pathophysiological processes in the heart and has prognostic value in the development of heart failure (HF) (see Wei Z.H., Li Y.Y., Huang S.Q. et al. Genetic variants in IL-33/ST2 pathway with the susceptibility to hepatocellular carcinoma in a Chinese population. Cytokine. 2019;118: 124-9. doi:10.1016/j.cyto.2018.03.036). It can be considered as a predictor of poor prognosis in heart failure (see Miftode R.S., Petris. A.O., Onofrei A.V. et al. The novel perspectives opened by ST2 in the pandemic: a review of its role in the diagnosis and prognosis of patients with heart failure and COVID-19. Diagnostics (Basel). 2021; 11 (2): 175. doi: 10.3390/diagnostics 11020175). This biomarker demonstrated high prognostic potential in patients with heart failure (see Dieplinger B., Januzzi J.L., Steinmair M., Gabriel C., Poelz W., Haltmayer M. et al. Analytical and clinical evaluation of a novel high-sensitivity assay for measuring soluble ST2 in human plasma - The Presage™ ST2 assay. Clinica Chimica Acta. 2009; 409 (1-2): 33-40) and was included in the ACC/AHA (American College of Cardiology/American Heart Association) guidelines for the diagnosis and treatment of heart failure as an additional component of risk stratification in CHF (see Yancy C.W., Jessup M., Bozkurt B., Butler J., Casey D.E., Drazner M.H. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013; 62 (16): el47-239).

The prognostic point for sST2 was defined as a concentration <33.2 ng/ml. Baseline parameters were generally comparable between men and women, with the exception of severe functional class of heart failure (FC HF) according to NYHA, due to more pronounced clinical manifestations of HF in women (Kamardinov D.Kh. et al., 2020).

In the multicenter prospective PHFS (Perm Heart Failure Study) study (1141 patients with CHF), sST2 proved to be a powerful marker of death risk. The risk of adverse outcomes was higher with its blood concentration >36.3 ng/ml compared with ≤22.3 ng/ml (relative risk (RR) 1.9; 95% confidence interval (CI): 1.3-2.9; p=0.002), and was more clearly observed in non-ischemic heart failure (RR=1.7: 95% CI 1.4-2.0; p<0.0001) (see Ky B., French B., McCloskey K., Rame J.E., Mcintosh E., Shahi P. et al. High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure. Circulation: Heart Failure. 2011; 4 (2): 180-7. DOI: 10.1161/CIRCHEARTFAILURE.110.958223).

Broch K. et al. (2012) in their study on the clinical basis of the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) project examined the relationship of sST2 with clinical outcomes in 1449 patients ≥60 years old with systolic (left ventricular ejection fraction (LVEF) ≤40%) heart failure of ischemic origin. Univariate analysis showed that baseline sST2 was significantly (p<0.001 for all cases) associated with the primary endpoint (composite of cardiovascular death/nonfatal myocardial infarction or stroke) and all predefined secondary endpoints in the CORONA study (all-cause death; cardiovascular death; sudden cardiac death; death related to worsening HF; coronary events; hospitalization for cardiovascular causes; hospitalization with worsening HF) (see Broch K, Ueland T, Nymo SH, Kjekshus J, Hulthe J, Muntendam P et al. Soluble ST2 is associated with adverse outcome in patients with heart failure of ischaemic aetiology. European Journal of Heart Failure. 2012; 14 (3): 268–77. DOI: 10.1093/eurjhf/hfs006).

In addition, based on the results of a meta-analysis that included 7 studies and summarized data on 6,372 patients with CHF, the authors convincingly show that sST2 is an independent predictor of death from all causes (OR = 1.75; 95% CI: 1.37-2.22; p < 0.001) and death from cardiovascular causes (OR = 1.79; 95% CI: 1.22-2.63; p < 0.001), thereby supporting the use of sST2 for stratification of the risk of death in outpatients with CHF. However, attention is drawn to the fact that the prognostic power of sST2 increases in the context of currently recommended optimal medical therapy (OMT) (see Aimo A., Vergaro G., Passino C., Ripoli A., Ky B., Miller W.L. et al. Prognostic Value of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure. JACC: Heart Failure. 2017; 5 (4): 280-6. DOI: 10.1016/j.jchf.2016.09.010).

Thus, ST2 has been shown in large studies to be a marker with high prognostic value, which suggests an important role for ST2 in the future as a marker for risk stratification of CHF and its complications in a multimarker approach strategy for patients in this category.

However, the use of the sST2 marker to predict the likelihood of developing cardiovascular events within 12 months after determining the sST2 biomarker, ng/ml in blood plasma in patients with CHF and frailty syndrome aged 80 years and older has not been described in the available literature.

The technical result of the proposed invention consists in developing a method that makes it possible to predict the likelihood of developing cardiovascular events, namely hospitalizations, rehospitalizations due to decompensation of chronic heart failure within 12 months after determining the sST2 biomarker, ng/ml in the blood plasma in patients aged 80 years and older, depending on the presence of frailty syndrome.

The technical result is achieved by the fact that during examination at the outpatient stage, all patients aged 80 years and older with chronic heart failure are identified for the criteria of frailty syndrome using the questionnaire "Age is not a hindrance", if questionable results are obtained: 3 or 4 points, an additional short battery of physical functioning tests is carried out, according to the results of which the presence of frailty syndrome is diagnosed, then the level of sST2 concentration, ng / ml in the blood plasma is determined and, if the concentration of sST2 increases to more than 55.6 ng / ml, the probability of hospitalization or rehospitalization due to decompensation of chronic heart failure is predicted within 12 months after determining the sST2 biomarker, ng / ml in the blood plasma.

The essential features of the claimed invention exhibited novel properties that were not clearly derived from the state of the art in this field and were not obvious to a person skilled in the art. No identical set of features was found in the reviewed literature. The proposed invention can be used in healthcare.

Based on the above, the invention should be considered as meeting the patentability conditions of “Novelty”, “Inventive step”, “Industrial applicability”.

We provide figures for a better understanding of the method.

Fig. 1. ROC curve of the ratio of diagnostic sensitivity and specificity values in assessing the risk of an unfavorable course of CHF based on the concentration of sST2 in the blood in patients with CHF against the background of CSA.

The novelty of the method is that the use of the sST2 marker in patients with CHF and frailty syndrome aged 80 years and older allows predicting the likelihood of developing cardiovascular events within 12 months after determining the sST2 biomarker, ng/ml in blood plasma.

It should be noted that in our observations, in patients with CHF and CSA aged 80 years and older, the risk of hospitalization or rehospitalization for HF was associated with an sST2 blood concentration exceeding 55.6 ng/ml. The diagnostic sensitivity of the prognostic decision was 91.7%, and the specificity was 75% (see Fig. 1).

The area under the ROC curve was 0.846±0.0436 (confidence interval 0.748–0.917) and differed from the reference diagonal line (z=7.938; p<0.001). According to the AUC assessment scale, an area under the ROC curve in the range of 0.8–0.9 indicated “very good” quality of the predictive model.

The relative risk of developing hospitalization for HF in patients with hypertension against the background of CSA and CHF when the serum concentration of sST2 exceeded 55.6 ng/ml was 3.7 (p<0.001) (see Table 1).

Thus, in patients with CHF and CSA, the concentration of sST2≥55.6 ng/ml indicates a high probability of risk of developing cardiovascular events, such as hospitalizations and rehospitalizations due to CHF.

The method is performed in the following way.

During outpatient examinations of patients with CHF aged 80 years and older, the presence of SSA is determined using the validated "Age is not a barrier" questionnaire (see the Clinical guidelines of the Russian Ministry of Health. Senile asthenia. 2020). It includes seven questions covering weight loss, sensory deficits, falls, symptoms of depression and cognitive impairment, urinary incontinence, and decreased mobility. The questionnaire can be completed by a nurse, non-medical personnel (e.g., volunteers), or the patient themselves. For each positive answer to a question, the patient scores one point, and for each negative answer, zero points. The maximum score for the questionnaire is seven.

Key (interpretation):

- 1-2 points - senile asthenia is absent;

- 3-4 points - preasthenia;

- 5 or more points - probable senile asthenia.

Next, all patients with an intermediate result (3-4 points) on the screening questionnaire undergo a brief battery of physical functioning tests (see the Clinical Guidelines of the Russian Ministry of Health. Frailty. 2020, Appendix G) to clarify their geriatric status. This battery includes determining balance in three different foot positions, assessing 4-meter walking speed, and a chair rise test. A patient scoring 10-12 points indicates no frailty, 8-9 points indicates pre-frailty, and 7 points or less indicates frailty. Based on these results, the presence of SSA is assessed.

Next, plasma sST2 concentrations (ng/ml) are measured in patients with SSA. An sST2 concentration of more than 55.6 ng/ml is used to predict the likelihood of hospitalization or rehospitalization for chronic heart failure decompensation within 12 months of plasma sST2 biomarker determination in patients aged 80 years and older with frailty syndrome.

We provide clinical examples of the application of the method

Clinical example 1

Patient N., 83 years old. During an outpatient examination, he complained of shortness of breath with minor physical exertion, a feeling of shortness of breath, increased fatigue, irregular heartbeat, and swelling of the lower extremities.

Upon examination, the general condition is satisfactory, breathing is vesicular, there are isolated dry wheezing, heart sounds are muffled, and there is symmetrical swelling of the feet.

From the anamnesis of the disease there is CHF for 11 years, currently - CHF with EF IIB stage III FC.

According to the “Age is not a barrier” questionnaire, the score is 5 points, which corresponds to the presence of SSA.

During the appointment, the patient's optimal drug therapy for heart failure was adjusted in accordance with the current 2020 clinical guidelines for chronic heart failure.

Determination of the concentration of sST2 in the blood = 59.8 ng/ml, which allows us to judge the high probability of the risk of developing a cardiovascular event, such as hospitalization and/or rehospitalization due to decompensation of chronic heart failure within 12 months after determining the sST2 biomarker, ng/ml in the blood plasma.

After 18 weeks, the patient was hospitalized in the emergency cardiology department with a clinical picture of acute coronary syndrome, which can be regarded as the development of acute decompensation of heart failure.

Clinical example 2

Patient N., 82 years old.

At the outpatient stage, during examination, the patient complains of shortness of breath with minor physical exertion, a feeling of lack of air, increased fatigue, and swelling of the lower extremities.

Upon examination, the general condition is satisfactory, breathing is vesicular, there are isolated dry wheezing, the heart sounds are muffled, rhythmic, there is symmetrical swelling of the feet.

History of CHF for 8 years, currently CHF with EF IIA stage III FC.

According to the “Age is not a barrier” questionnaire, the score is 6 points, which corresponds to the presence of SSA.

During the appointment, the patient's optimal drug therapy for heart failure was adjusted in accordance with the current 2020 clinical guidelines for chronic heart failure.

Determination of the concentration of sST2 in the blood = 58.1 ng/ml, which allows us to judge the high probability of the risk of developing cardiovascular events, such as hospitalization or rehospitalization due to decompensation of chronic heart failure within 12 months after determining the sST2 biomarker, ng/ml in blood plasma.

Three weeks after discharge from the hospital for treatment of acute heart failure, the patient was readmitted to the emergency cardiology department with complaints of irregular heartbeat, and an ECG showing paroxysmal atrial flutter, which can be regarded as the development of acute decompensation of heart failure.

Clinical example 3

Patient M., 84 years old. Upon examination, she complains of shortness of breath at rest, a feeling of shortness of breath, increased fatigue, and swelling of the lower extremities.

Upon examination, the general condition is satisfactory, breathing is vesicular, there are isolated dry wheezing, the heart sounds are muffled, rhythmic, there is symmetrical swelling of the feet.

History of CHF for 10 years, currently CHF with EF IIB stage III FC.

According to the “Age is not a barrier” questionnaire, the score is 5 points, which corresponds to the presence of SSA.

During the appointment, the patient's optimal drug therapy for heart failure was adjusted in accordance with the current 2020 clinical guidelines for chronic heart failure.

Determination of the concentration of sST2 in the blood = 43.6 ng/ml, which does not allow us to judge the high probability of the risk of developing cardiovascular events, such as hospitalization or rehospitalization due to decompensation of chronic heart failure within 12 months after determining the sST2 biomarker, ng/ml in the blood plasma.

Over the course of 12 months, while following the recommended therapy, no cardiovascular events, such as hospitalization or rehospitalization for decompensated chronic heart failure, were observed. The patient's condition remained stable.

This method was used to predict the risk of developing cardiovascular events, such as hospitalization and/or rehospitalization due to decompensation of chronic heart failure within 12 months after determining the sST2 biomarker, ng/ml in blood plasma in 32 patients with CHF and frailty syndrome aged 80 years and older.

The method is easy to use and can be implemented in any medical institution with the appropriate profile.

The technical and economic efficiency of the method lies in the fact that its use allows for a high-accuracy prediction of the risk of developing cardiovascular events, such as hospitalization and/or rehospitalization due to decompensation of chronic heart failure within 12 months after determining the sST2 ng/ml biomarker in blood plasma in 32 patients with CHF and frailty syndrome aged 80 years and older.

Claims (1)

A method for predicting the probability of hospitalization or rehospitalization due to decompensation of chronic heart failure within 12 months in patients with frailty syndrome aged 80 years and older, characterized by determining the level of sST2 concentration in blood plasma and, if the sST2 concentration increases by more than 55.6 ng/ml, predicting the probability of hospitalization or rehospitalization due to decompensation of chronic heart failure within 12 months after determining the sST2 biomarker in patients with frailty syndrome aged 80 years and older.