Markers of Poor Prognosis in Non-ST Segment Elevation Acute Coronary Syndromes without Revascularization: A 3-year Survival Analysis

Introduction: The non-ST elevation-acute coronary syndrome (NSTE-ACS) accounts for more than 50% of the total number of patients with ACS. The mortality rates after non-ST-elevation myocardial infarction (MI) are not significantly different when compared with patients with ST-segment elevation MI. The aim of the present study was to investigate whether the assessment of clinical, laboratory, and instrumental data during hospital stay provides any additional independent information in predicting the 3-year major cardiac events after NSTE-ACS. Patients and Methods: We observed 490 consecutive patients, who were admitted to the emergency cardiology department with NSTE-ACS. The patients’ baseline characteristics, blood analysis, left ventricle (LV), and renal function data were assessed and analyzed. The median followup time was 36 months. The endpoint was cardiovascular death. Results: The results of our study show that the risk of cardiovascular death during the 3 years’ followup after multivariate adjustment increases with older age (>64 years), history of diabetes, prior MI and history of angina pectoris, lower ejection fraction (<50%), degree of myocardial hypertrophy (the thickness of the interventricular septum >1.25 mm) of the LV and the degree of diastolic dysfunction (E-wave deceleration time <150 ms), silent myocardial ischemia during first 24-h, high pulse pressure on day 1 (>49 mm Hg), glucose level >7.5 mmol/l on admission, and moderate kidney dysfunction (creatinine level and its clearance <60 ml/min). Conclusion: In patients with NSTE-ACS, we report the cardiovascular death risk factors within the 3-year follow-up period in the present study. We, thus, conclude that it is important to identify the patients with high risk of future cardiovascular complications.


Introduction
Coronary artery disease remains one of the leading causes of death worldwide. Approximately 1 million new and recurrent acute myocardial infarctions (AMI) occur annually in the United States. [1] Each year in Ukraine, more than 50,000 patients experience an acute coronary event [2] and more than 50% of them have a non-ST elevation acute coronary syndrome (NSTE-ACS) with increasing of the proportion of NSTE-ACS events per year. [3] Mortality rates after AMI have decreased over the past decades but differ between ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI) patients. [4] Data from randomized trials have shown that hospitalized patients with NSTEMI have a lower risk of death during the 1 st few weeks after MI whereas are at the higher risk for cardiovascular outcomes over the long-term follow-up than those with STEMI. [5,6] Patients with ACS should undergo risk stratification to predict those who are at high risk for short-and long-term adverse outcomes. Among patients with NSTE-ACS, which includes NSTEMI and unstable angina (UA), risk stratification begins soon after admission to detect patients at high risk during the early Journal of Medical Research and Innovation Volume 2, Issue 2, e000139 Direct Access: https://jmri.org.in/jmri/article/view/139 2 hospital phase. Subsequent risk stratification is aimed to predict patients being at increased risk after discharge. [7] The aim of the present study was to investigate whether the assessment of clinical, laboratory, and instrumental data during hospital stay provides additional independent information in predicting 3-year major cardiac events after NSTE-ACS.

Study population
In an observational, retrospective cohort study, a total of 490 consecutive patients admitted to the emergency cardiology department with a diagnosis of NSTE-ACS were included. The definition of NSTE-ACS was based on the following criteria: (a) Prolonged (>20 min) anginal pain at rest; (b) and electrocardiographic (ECG) findings suggestive of ischemia: ST segment depression (>1 mm) or inversion of the T wave (>1 mm); and/or (c) positive biomarkers of necrosis (troponins or MB fraction of creatine kinase).

Inclusion criteria
The following criteria were included in the study:

Study protocol
Each patient underwent a physical examination with measuring of blood pressure (BP), heart rate, body mass index, and followed by standard diagnostic tests (ECG, biomarkers). Furthermore, we analyzed complications during in-hospital period and laboratory data (C-reactive protein, fibrinogen, erythrocyte sedimentation rate [ESR], white blood cells [WBC], and creatinine) on the day 1 and on the day 10. Two-dimensional echocardiography was performed on the day 1 after admission to the hospital and Holter ECG monitoring and heart rate variability (HRV) on the days 1, 3, 7, and 10 of in-hospital stay. Renal function was estimated using CrCl on admission and on the day 10 using the Cockcroft-Gault formula. Treatment of all patients was according to the National and European recommendations and standards. [7] This study was approved by the Ethics Committee at the National Scientific Center, the M. D. Strazhesko Institute of Cardiology.

Endpoints
The endpoint was a composite of cardiovascular death, non-fatal MI, UA, and percutaneous coronary intervention with coronary artery stenting and coronary artery bypass grafting. Information regarding adverse events was obtained from patients or family doctors or patients' relatives during phone calls.

Statistical analysis
Statistical analysis was assessed with "SPSS 13.0" software using Student's t-test and χ 2 -test. Data were reported as means with standard deviation, and the categorical variables were expressed as numbers with percentages. A multivariate Cox regression analysis was performed for the confounding effects, and odds ratios and 95% confidence intervals were calculated. A value of P < 0.05 was considered statistically significant.

Patients' characteristics
All prognostic analyses in the present study were carried out using data from 490 patients. The baseline characteristics of the patients and medications are summarized in Tables 1 and 2 respectively.

Endpoint events
The median follow-up time was 36 months (interquartile range: 32-39 months). The endpoint was monitored every 6 months, and the data of 94.90% of patients (n = 465) were available for analyses. Patients, who died during in-hospital stay and those without contact during follow-up, were excluded from analyses. Endpoint events during 3-year follow-up are presented in Table 3.
Results of our study show that the risk of cardiovascular death during 3-year follow-up after multivariate adjustment increases with older age (>64 years), history of diabetes, prior MI, and history of angina pectoris [ Figure 1].
Lower ejection fraction (EF) (<50%), degree of myocardial hypertrophy (the thickness of the interventricular septum >1.25 mm) of the left ventricle (LV), and the degree of diastolic dysfunction (E-wave deceleration time [DT] <150 ms) were identified as independent predictors of cardiovascular mortality also [ Figure 2]. Journal of Medical Research and Innovation Volume 2, Issue 2, e000139 Direct Access: https://jmri.org.in/jmri/article/view/139 3 We hypothesized that depressed HRV could have a negative impact on cardiovascular death by suppressing parasympathetic and augmenting sympathetic components of HRV. Highfrequency (PH <18.5) and low-frequency (PL >81) components of HRV and total power (PT >15) were determined by spectral analysis [ Figure 3].
Silent myocardial ischemia (SMI) -objectively documented ischemia in the absence of chest discomfort or an another anginal equivalent -is a major risk factor of poor prognosis. [8] We studied SMI during days 1, 3, 7, and 10 by 24 h Holter ECG monitoring, and only SMI during the first 24 h had a negative predictive impact.    Clinical history of arterial hypertension in MI is well known as a negative prognostic factor. [9] In our study, we established that low mean and high pulse pressure on the day 1 were significantly associated with cardiovascular mortality [ Figure 4].
The high ESR levels on admission are found to be related to poor short-and long-term survival. Therefore, ESR evaluation on admission may be helpful to identify patients with a poor prognosis. In our study value, ESR >13 mm/h on admission was a cutoff point according to the Cox regression analyses.
Patients either with or without a prior history of diabetes mellitus (DM) may present with hyperglycemia during ACS, and hyperglycemia on admission remains an independent predictor of post-discharge mortality. Our data confirmed that glucose level >7.5 mmol/l on admission could be a negative risk factor for those patients without a history of DM.
Renal function should be measured in all patients with NSTE-ACS during 1 st h because it is important for dose adjustment of drugs and contrast agents released through the kidneys. On the other hand, estimated glomerular filtration rate (GFR) has a powerful relationship between the severity of renal dysfunction and poor outcomes. In our study, survival analysis showed that patients with moderate dysfunction (CrCl <60 ml/min) had a higher rate of cardiovascular death than patients with CfCl >60 ml/min [ Figure 5].

Discussion
Optimal, evidence-based treatment after NSTE-ACS can only reduce the risk of an event. Even optimally treated patients face a residual risk of adverse cardiovascular outcomes due to the underlying disease process and a number of comorbidities. [10] Therefore, all post-NSTE-ACS patients should receive betablockers and statins in recommended doses permanently, if not contraindicated. [11] Patients also require medications to modify risk factors, such as antihypertensive medications to achieve target BP, angiotensin-converting enzyme inhibitors for left ventricular dysfunction, and antihyperglycemic agents to maintain a goal of glucose level. [12] In our study, we investigated the risk factors for the stratification of long-term outcomes. It is very important to identified patients with a high risk of future cardiovascular complications after discharge. The results of this study showed that older age, history of MI, previously diagnosed angina pectoris, diabetes, systolic dysfunction, HRV abnormality, elevated mean pulse BP and blood glucose findings at the time of hospital admission, and lower CrCl findings were the main factors significantly associated with an adverse long-term prognosis following hospital discharge for patients with NSTE-ACS after multivariate adjustment for the demographic characteristics, comorbidities, and hospital complications.
Older age and the presence of comorbidities have been recognized as critical factors in predicting the clinical outcomes in patients with ACS. In the present study, it was proved that existing coronary heart disease, DM, and renal disease were the main comorbidities led to a higher incidence of mortality. In an another large study, it was found that independent predictors of early mortality in NSTE-ACS patients included old age above 60-year-old, Killip class, female gender, LV dysfunction, and renal failure. [12] In another such study, it was confirmed that DM, in addition to age and systolic LV dysfunction, was found to be independent predictors of early mortality in those patients. [13] There are studies that suggest that hemodynamic measures can predict mortality, whereas the evidence of the prognostic value of hemodynamic measures in NSTE-ACS patients is limited. This research demonstrated the influence of LV hypertrophy and the degree of diastolic dysfunction on CV death, and our data coincide with the results of other authors. [14] LVEF is a valid indicator of myocardial function and has shown by multiple studies to be an established predictor of adverse 5 clinical outcomes. Data of a prospective cohort study showed that LVEF ≤50% was associated with high rates of adverse events, including death. [15] Low HRV is usually considered as a negative long-term prognostic factor after an ACS. In our group of patients with a recent ACS, abnormal autonomic parameters have been correlated with long-term outcomes. These results support the significant prognostic value of traditional HRV parameters, and HRV measured close to the ACS onset may assist in risk stratification. [16] According to the recent publications, the long-term mortality for patients with NSTE-ACS has been related to the extent of their comorbid disease burden. [17] In the present study, patients with NSTE-ACS were more likely to have several previous comorbid diseases, especially patients to have decreased survival if they had a history of angina pectoris, prior MI, and diabetes. Similarly, we found that systolic dysfunction and heart rate abnormalities were associated with decreased survival after hospital discharge.
If established risk assessment methods are not used, it leads to underestimate risk in high-risk patients and overestimate risk in low-risk patients. [18] In addition, physicians tend to estimate the risk based on the intensity of treatment received during the ACS. In particular, physicians underestimate risk associated with age and may consider younger ACS patients as having a more aggressive disease phenotype than older patients, while underestimating the impact of age-associated accumulated coronary artery damage. [19] Therefore, it is important that physicians should use validated objective measures of risk when assessing ACS patients.

Limitations
Our study has several limitations that should be considered when interpreting the present results. This was a single-center and observational uncontrolled study. The samples were restricted to patients discharged from our hospital with a successful follow-up, which may have resulted in selection biases and conclusions with limited generalizability. There was a tendency for cardiologists to perform conservative treatment for high-risk patients, which might have affected the final results. Finally, this study cannot exclude possible residual confounding by other measured and/or unmeasured factors including the treatment decisions of patients when NSTE-ACS occurred, which is an important source of prognosis.
There are currently limited data to guide clinical decisionmaking around optimal secondary preventive therapies in NSTE-ACS patients who survive after hospital discharge. On-going risk assessment is important in all post-MI patients, and clinicians should use the objective measures of evaluation whenever it possible, to avoid over-or under-estimating future risk.

Conclusion
Our findings suggested that, in patients with NSTE-ACS, the cardiovascular death risk factors for the 3-year follow-up were as follows: • Demographic and clinical factors: Age, history of MI, history of angina pectoris, and DM. • Instrumental: LV EF, LV hypertrophy, low DT, depressed HRV, and silent ischemia according to the results of Holter ECG monitoring and median pulse BP. • Laboratory: ESR, glucose level, and GFR.