Article, Cardiology

Usefulness of the thrombolysis in myocardial infarction risk index in acute heart failure: a pilot study

a b s t r a c t

Background: Risk stratification in acute heart failure is vital for both physicians and paramedical personals. Thrombolysis in Myocardial Infarction risk index (TRI) and modified TRI (mTRI) are novel and simple pre- dictive risk indices that have been examined in patients with acute coronary syndrome.

Objective: In the current study, we evaluated the relationship among TRI, mTRI, and mortality in patients with AHF.

Methods: A total of 293 patients with AHF were retrospectively analyzed. The patients were divided into 2 groups: group 1 consisted of patients who survived and group 2 consisted of patients who died during a follow-up period of 120 days. Multivariate hierarchical logistic regression analysis was performed to evaluate the relationship among TRI, mTRI, and mortality.

Results: All causes of death occurred in 84 patients (28.6%). Thrombolysis in myocardial infarction risk index was significantly higher in patients who died during follow-up (20.2 +- 12.4 vs 14.8 +- 8.9). The new risk score showed good predictive value for 120-day mortality. Before laboratory analysis, in-multivariate hierarchical lo- gistic regression analysis TRI remained as an independent risk factor for mortality (odds ratio, 2.56; P b .001). After the laboratory analysis, despite the fact that TRI has lost its predictive value, mTRI remained an independent risk factor for mortality (odds ratio, 2.08; P = .01).

Conclusion: The TRI is a simple and strong predictor of all-cause mortality in patients who were admitted with AHF. The current study reveals for the first time the strong predictive value of TRI in patients with AHF.

(C) 2016

Introduction

Acute heart failure is a common health problem and is charac- terized by poor prognosis. It is followed by a rehospitalization rate up to 40%. Patients living with congestive heart failure (CHF) experience ap- proximately 1 million annual hospitalizations [1]. Despite several criti- cal steps forward in the management of chronic CHF, the area of AHF has remained relatively stagnant [2]. There have been some different simple novel biomarkers that were found to be significantly associated with long-term mortality such as brain-type natriuretic peptide, serum soluble ST2 receptor, highly sensitive troponin, and others [3,4]. These novel biomarkers are usually obtained after laboratory analysis. Although these scoring systems have many advantages, they require laboratory analysis to perform scoring. Therefore, physicians or para- medical personnel need an easily accessible, cost-effective, and non- laboratory-dependent method to carry out risk stratification to

* Corresponding author at: Dr Siyami Ersek Hospital, Tibbiye Str No. 25, Uskudar, Istan- bul, Turkey. Tel.: +90 2165424444; fax: +90 2163379719.

E-mail address: [email protected] (M. Keskin).

determine the severity and prognosis of AHF patients [5]. The thrombol- ysis in myocardial infarction (TIMI) risk index (TRI) is a simple, general- izable, and well-validated instrument based on age and initial vital signs [6]. Recently, the TRI has been proven to be useful in many studies due to its ability to predict mortality and the ease of assessment and scoring with fewer parameters (age, blood pressure [BP], heart rate [HR], etc) in patients with acute coronary syndrome (ACS) [7]. However, many stud- ies have examined the association among the coronary artery disease, ACS, and TRI; there is not a recent study evaluating the prognostic value of TRI in patients with AHF. Thus, the objective of the current study is to evaluate the predictive value of TRI in patients with AHF. (See Figs. 1 and 2.)

Methods

A total of 401 patients (46.2 +- 14.1) who fulfilled the criteria of AHF were admitted to the emergency department (ED) of a tertiary center from January 2013 to December 2014 were evaluated retrospectively. The patients were divided into 2 groups: group 1 consisted of patients who survived during a follow-up period of 120 days and group 2

http://dx.doi.org/10.1016/j.ajem.2016.08.047

0735-6757/(C) 2016

Fig. 1. Box plot showing the distribution of TRI values of the 2 groups.

consisted of patients who died during a follow-up period of 120 days. All of the study population had completed 120-day follow-up data. Conges- tive heart failure is defined as a syndrome in which patients have Typical symptoms (eg, breathlessness, ankle swelling, and fatigue) and signs (eg, elevated jugular venous pressure, pulmonary crackles, and displaced apex beat) resulting from an abnormality of cardiac structure or function [8]. The current study was based on the patients with AHF. A total of 109 patients who had an affecting factor that could change the survival including systemic disease and use of medical treatment with chemotherapy, evidence of any concomitant inflammatory disorder,

acute and chronic infection, use of glucocorticoid therapy within the past 3 months, ACS and percutaneous coronary intervention in the past 6 months, and secondary hypertension were excluded. This study was approved by the institutional ethical and scientific review.

Risk scores

Thrombolysis in myocardial infarction risk index and modified TRI (mTRI) scores were calculated in all patients. The TRI is calculated using the following equation: TRI = (HR x [age/10]2)/systolic BP. The

Fig. 2. Box plot showing the distribution of mTRI values of the 2 groups.

mTRI is calculated using the following equation: mTRI = (TRI x blood urea nitrogen [BUN])/10.

Table 1

Baseline characteristics, laboratory findings, and TRI and mTRI in AHF patient groups

Data sources

Clinical, demographic, historical, angiographic, treatment, and labo- ratory data were obtained from the hospital’s medical database. Labora- tory analysis was performed at the time of admission. All patients were evaluated for the presence of Cardiovascular risk factors such as hyper- tension, diabetes mellitus , previous coronary artery bypass graft (CABG), and Atrial fibrillation . Evaluation of mortality was obtained from hospital’s medical database or by follow-up interviews (directly or by telephone). The primary end point was 120-day mortality.

Definitions

Hypertension was defined as systolic BP greater than or equal to 140 mm Hg and/or Diastolic BP greater than or equal to 90 mm Hg, pre- viously diagnosed hypertension, or use of any antihypertensive medica- tions. Diabetes mellitus was defined as fasting plasma glucose levels more than 126 mg/dL in multiple measurements, previously diagnosed DM, or use of antidiabetic medications such as oral antidiabetic agents or insulin. Echocardiogram was performed by trained cardiologists, and left ventricular ejection fraction (LVEF) was calculated using the Simpson method [9]. The drugs were administered during the hospital- ization according to the European Society of Cardiology Guidelines [8].

Parameter Group 1, patients alive at follow-up (n = 209)

Demographic and clinical variables

Age (y)

44.06 +- 12.43

50.31 +- 16.99

.003

Sex (female)

39 (19.1)

19 (22.6)

.50

Hypertension

71 (34.0)

32 (38.1)

.48

Diabetes

34 (16.7)

19 (22.6)

.23

Previous CABG

20 (9.6)

6 (7.1)

.52

Atrial fibrillation

26 (12.4)

15 (17.9)

.26

Medications before hospi

ACE inhibitor

talization

153 (73.2)

60 (71.4)

.99

ARB

42 (20.1)

9 (10.7)

.07

?-Blocker

201 (96.2)

70 (83.3)

b.001

Spironolactone

174 (83.3)

64 (76.2)

.30

Furosemide

152 (72.7)

73 (86.9)

.003

Digoxin

119 (56.9)

52 (61.9)

.31

Physical examination and laboratory paramete Systolic BP (mm Hg) 122.37 +- 20.97

rs

118.97 +- 23.13

.22

Diastolic BP (mm Hg)

77.11 +- 12.97

74.69 +- 12.39

.14

HR (beats per minute)

86.02 +- 15.95

88.60 +- 16.78

.22

LVEF (%)

26.55 +- 9.63

24.66 +- 10.80

.15

Hemoglobin (g/dL)

14.11 +- 1.84

13.20 +- 2.11

b.001

Sodium (mEq/L)

139.57 +- 2.77

136.19 +- 4.90

b.001

Potassium (mEq/L)

4.55 +- 0.47

4.38 +- 0.65

b.001

BUN (mg/dL)

18.22 +- 9.22

28.31 +- 16.64

b.001

Creatinine (mg/dL)

0.96 +- 0.27

1.14 +- 0.44

b.001

CRP

2.75 +- 8.38

17.04 +- 26.64

b.001

TIMI risk indices TRI

14.89 +- 8.91

20.27 +- 12.49

b.001

mTRI

28.41 +- 24.64

64.53 +- 69.44

b.001

Group 2, patients who died P

during follow-up (n = 84)

Statistical analysis

Analyses were performed using SPSS software, version 20.0 (IBM, Armonk, New York). Continuous variables were expressed as the mean +- SD, and categorical variables were expressed as percentages. Comparisons between categorical variables between the TRI groups were performed using the ?2 or Fisher exact test. Independent-sample t test was used in the analysis of continuous variables. To analyze the prediction for 120-day mortality, data from the admission parameters were used as independent variables. The univariate relationship be- tween baseline characteristics and 120-day mortality was assessed by univariate hierarchical logistic regression analysis. Multivariate analysis by stepwise logistic regression models (backward elimination) tested variables that were significant at P b .1 in the univariate analysis. Statis- tical significance was defined as P b .05.

Results

A total of 293 patients (mean age, 46.2 +- 14.1 years; women 19.7%) with AHF were included. There was significant difference in terms of age (P = .003) among the groups, whereas there was no significant differ- ence in terms of sex (P = .50), hypertension (P = .48), DM (P = .23), previous CABG (P = .52), and AF (P = .26). The patients’ baseline char- acteristics, medications, physical examination, laboratory parameters, and TRIs are listed in Table 1. In medication, 2 groups had similar treat- ments except ?-blocker and furosemide treatments (P b .001 and P =

.003, respectively). In physical examination, 2 groups had similar systol- ic and diastolic BPs and HR. In laboratory parameters, 2 groups had sim- ilar LVEF, whereas group 1 had higher hemoglobin and sodium and Potassium levels, and group 2 had higher potassium, BUN, creatinine, and C-reactive protein levels (all P b .001). Group 2 had significantly higher TRI and mTRI values (20.2 +- 12.4 vs 14.8 +- 8.9 and 64.5 +- 69.4 vs 28.4 +- 24.6, respectively). Before and after the bio- chemical analyses, 2 different hierarchical logistic regression analyses were performed. In the first analysis, the univariate predictors of 120- day mortality were LVEF, AF, furosemide treatment, age, and TRI. By multivariate hierarchical logistic regression analysis, the 2 independent factors that increased the risk of 120-day mortality were TRI (odds ratio [OR], 2.56; confidence interval [CI], 2.14-2.79), age (OR, 1.07; CI, 1.01-

Statistically significant findings are in boldface. Abbreviations: ACE, angiotensin- converting enzyme inhibitor; ARB, angiotensin receptor blocker.

1.12), and furosemide treatment (OR, 2.03; CI, 1.29-4.39). In the second analysis, after the biochemical results, the univariate predictors of 120- day mortality were HR, furosemide treatment, LVEF, total cholesterol, alanine aminotransferase, aspartate aminotransferase, BUN, creatinine, sodium, potassium, CRP, age, and mTRI. By multivariate hierarchical lo- gistic regression analysis, the 7 independent factors that increased the risk of 120-day mortality were HR (OR, 1.06; CI, 0.98-1.12), BUN (OR, 0.98; CI, 1.01-1.11), sodium (OR, 0.75; CI, 0.68-0.82), potassium (OR,

0.63; CI, 0.32-0.87), CRP (OR, 1.08; CI, 1.05-1.14), age (OR, 1.04; CI,

1.01-1.08), and mTRI (OR, 2.08; CI, 1.71-2.52). (See Tables 2 and 3.)

Discussion

This retrospective observational study of patients with AHF demon- strated a significant relationship among mTRI, TRI and mortality (120 days). Group 2 had significantly higher TRI value. After a further logistic regression analysis, TRI remained as an independent risk factor for mor- tality before the biochemical analysis. After the laboratory analysis, a

Table 2

Univariate predictors and multivariate model for mortality at 120 days

Univariate analysis

P

Multivariate analysis

P

OR, 95% CI

Sex

.57

LVEF

.11

Atrial fibrillation

.15

Hypertension

.40

Diabetes

.21

Previous CABG

.25

Systolic BP

.37

Diastolic BP

.49

HR

.25

Furosemide

.005

Furosemide

.007

2.03 (1.29-4.39)

Age

b.001

Age

.004

1.07 (1.01-1.12)

TRI

b.001

TRI

b.001

2.56 (2.14-2.79)

Only parameters that could be readily obtained at admission were included in this analysis.

Table 3

Univariate predictors and multivariate model for mortality at 120 days

Univariate analysis

P

Multivariate model

P

OR (95% CI)

HR

.004

HR

.02

1.06 (0.98-1.12)

Furosemide

.002

LVEF

.42

Hemoglobin Total cholesterol

Alanine aminotransferase Aspartate aminotransferase

BUN

.004 b.001 b.001 b.001

b.001

BUN

.01

0.98 (1.01-1.11)

Serum creatinine

b.001

Sodium

b.001

Sodium

.009

0.75 (0.68-0.82)

Potassium

.007

Potassium

.02

0.63 (0.32-0.87)

CRP

b.001

CRP

.004

1.08 (1.05-1.14)

Age

b.001

Age

.02

1.04 (1.01-1.08)

mTRI

b.001

mTRI

.01

2.08 (1.71-2.52)

All clinically relevant parameters were included in the model. Only parameters that reached statistical significance at univariate analysis were given in the leftmost column.

second logistic regression analysis was performed to reveal the inde- pendent risk factors for mortality. According to these results, mTRI remained as an independent risk factor for overall mortality for 120 days. Because of serious predictive value of biochemical and complete blood count analysis, TRI did not remain as an independent risk factor for overall mortality. Modified TRI includes BUN which is very impor- tant in patients with AHF. This suggests that the significant predictive value of mTRI is partially derived from BUN.

Acute heart failure refers to rapid onset or worsening of symptoms and/or signs of heart failure. It is a life-threatening medical condition re- quiring urgent evaluation and treatment, typically leading to urgent hospital admission. Acute heart failure comes with poor prognosis. De- spite the recent disease-specified therapies and survival improvements for CHF, hospitalization for AHF increases gradually [10]. Acute heart failure is a common presentation in EDs. Currently, there is not a com- mon guideline to help stratify patients at high risk for death or other sig- nificant morbidities [11,12]. In the era of advanced cardiovascular diagnosis and treatment, physicians commonly rely on laboratory anal- ysis to reveal any complication such acute kidney and hepatic failure, electrolyte disturbances, underlying infective disease, and others. The 2013 American College of Cardiology and American Heart Association guidelines did not mention of a management in ED and only suggested that intravenous diuretic should be administered urgently [13]. We ob- viously need an easier and more validated risk score for patients with AHF. Acute heart failure requires a rapid evaluation and/or referral of patient urgently. Some authors have developed stratification indexes for patients with AHF; however, those were commonly laboratory de- pendent [11,14]. Thrombolysis in myocardial infarction risk index is a novel and cheap risk index which was used recently as a prognostic and predictive factor in patients with ACS for mortality. Acute coronary syndrome and AHF commonly have similar precipitating and prognostic factors such as age, hypotension, and tacyhcardia in admission [15,16]. Thrombolysis in myocardial infarction risk index was found as a signif- icant predictive risk index for short- and long-term mortalities in some large cohorts and studies of patients with ACS [4-6,17]. Despite the pre- dictive value of TRI in ACS, it has not been evaluated in patients with CHF or AHF.

Hypotension is a worsening factor for AHF and associated with in- creased mortality. Patients with lower systolic BP that needs early ino- tropic treatment have a ratio of 26% Inhospital mortality. Age is another risk factor which associated with worse outcomes and high mortality [18]. Higher HR also brings higher myocardial consumption. Acute heart failure patient could also benefit from HR reduction, as myocardial oxygen consumption and oxidative stress are related to tachycardia. Heart rate reduction with ?-blockers or ivabradine is strict- ly recommended in patients with acute or chronic CHF [19,20]. Throm- bolysis in myocardial infarction risk index is calculated using HR,

systolic BP, and age and considered as a valuable risk index in patients with ACS recently. These 3 clinical parameters are also important in AHF as stated before. After the laboratory analysis, mTRI which was cal- culated using TRI and BUN showed a significant predictive value.

Conclusion

Thrombolysis in myocardial infarction risk index is a novel and sim- ple risk index that can be calculated using vital signs (systolic BP and HR) and age. However, this risk index is recently developed and consid- ered as an important predictive index in patients with ACS; it has not been evaluated in patients with AHF. Our results demonstrate for the first time the predictive value of TRI in patients with AHF. This risk index can be used as a rapid tool for easy risk stratification in patients with AHF. Beyond the EDs, this clinical index could be implemented by paramedical team in the prehospital setting. To put forward the in- teraction between the TRI and AHF, some additional and large-volume studies need to be established.

Study limitations

Our study has several limitations. First, this is a single-center, retro- spective, and observational study based on relatively small number of patients. Second, TRI was designed to provide a prehospital and initial risk estimation during the first patient contact. It does not associate the impact of therapy, comorbidity, or baseline treatments with out- come. Third, SBP measurements were noninvasive. Fourth, the patients who underwent cardiac transplantation were not included.

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