INTRODUCTION — All patients with non-ST elevation acute coronary syndromes (NSTEACS), which includes unstable angina and non-ST elevation myocardial infarction (NSTEMI), should undergo early and late risk stratification. This process impacts decision making regarding treatment and provides the patient with some sense of what the future holds.
The general approach to risk stratification for patients with NSTEACS will be reviewed here. Risk stratification is accomplished with the use of validated risk prediction models that include the most important predictors of outcome. These individual predictors are discussed separately. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes".)
It should be noted that this topic addresses risk stratification after a common atherosclerotic plaque rupture MI. However, there are many different pathogenetic mechanisms for NSTEACS, and prognosis will vary based on the mechanism. Examples of other mechanisms of NSTEACS include spontaneous coronary artery dissection and oxygen supply-demand mismatch. (See "Spontaneous coronary artery dissection" and "Diagnosis of acute myocardial infarction", section on 'Joint Task Force definitions'.)
Risk stratification for patients with an acute ST elevation MI (STEMI) and for those at risk for life-threatening arrhythmias is discussed separately. (See "Risk stratification after acute ST-elevation myocardial infarction" and "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".)
VERY HIGH-RISK PATIENTS — Individuals with any one of the following clinical characteristics are deemed to be at such high risk that formal early risk stratification is not necessary. These patients typically need to proceed to urgent coronary angiography:
●Cardiogenic shock
●Overt heart failure (HF) or severe left ventricular dysfunction
●Recurrent or persistent rest angina despite intensive medical therapy
●Hemodynamic instability due to mechanical complications (eg, acute mitral regurgitation, ventricular septal defect)
●Unstable ventricular arrhythmias
This issue is discussed separately. (See "Non-ST-elevation acute coronary syndromes: Revascularization".)
EARLY RISK STRATIFICATION TOOLS — Patients with NSTEACS who lack features indicating the need for immediate intervention (see 'Very high-risk patients' above) should undergo early risk stratification as soon as possible after the diagnosis is secured to identify individuals who should be treated with an early invasive strategy. We recommend risk stratification, using validated risk prediction tools, of all such patients, particularly those with ST-depression on the electrocardiogram or elevated cardiac biomarkers. We use the Global Registry of Acute Coronary Events (GRACE) or Thrombolysis in Myocardial Infarction (TIMI) tools, as they are derived from large populations and have been well validated in this setting [1].
However, most of these individuals undergo early angiography in the absence of a contraindication in our hospitals. (See "Non-ST-elevation acute coronary syndromes: Revascularization".)
The results of early risk stratification are also used to predict 30-day and long-term outcomes. For example, for lower-risk patients with chest pain, but no ST-segment deviation on the first electrocardiogram, and normal troponin levels, the risk of death or myocardial infarction may be as low as 6.7 percent at one year [2].
The following are validated risk prediction models or tools that can be used early into the care of patients hospitalized with NSTEACS. These tools differ somewhat in their populations, outcomes, and time frames.
TIMI risk score — Analysis of data from the TIMI 11B and ESSENCE trials found seven variables to be independently predictive of outcome in patients with unstable angina or an NSTEMI. These criteria were defined as the TIMI risk score (figure 1). To calculate the score, a value of 1 is assigned when each variable was present and 0 when it was absent [3]:
●Age ≥65 years
●Presence of at least three risk factors for coronary heart disease (CHD)
●Prior coronary stenosis of ≥50 percent
●Presence of ST segment deviation on admission ECG
●At least two anginal episodes in prior 24 hours
●Elevated serum cardiac biomarkers
●Use of aspirin in prior seven days
A higher TIMI risk score correlated significantly with increased numbers of events (all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring revascularization) at 14 days (calculator 1):
●Score of 0/1 – 4.7 percent
●Score of 2 – 8.3 percent
●Score of 3 – 13.2 percent
●Score of 4 – 19.9 percent
●Score of 5 – 26.2 percent
●Score of 6/7 – 40.9 percent
The TIMI risk score has been validated in multiple cohorts [4,5].
A similar predictive value has been noted for post-discharge events at six weeks [6] and for major cardiac events at 30 days in patients who have undergone percutaneous coronary intervention (PCI). (See "Non-ST-elevation acute coronary syndromes: Revascularization".)
Not surprisingly, higher TIMI risk scores have been correlated with more severe angiographic disease. In an analysis from PRISM-PLUS, increasing TIMI risk scores from 0 to 2 (low risk) to 5 to 7 (high risk) were associated with progressive increases in the frequency of high-risk angiographic findings such as severe (>70 percent) culprit stenosis (from 58 to 81 percent), multivessel disease (43 to 80 percent), visible thrombus (30 to 41 percent), and left main disease [7].
The TIMI risk score can also identify patients most likely to benefit from particular therapies:
●In TACTICS-TIMI 18, only patients at moderate to high risk (score ≥3) benefited from an early invasive strategy [8]. The presence of biomarker elevation and ST segment deviation are two of the TIMI risk score variables. However, a later analysis from TACTICS-TIMI 18 showed that the degree of troponin elevation and magnitude of ST segment deviation were independent predictors of an adverse outcome and of benefit from an early invasive strategy [9].
●In PRISM-PLUS, only patients with a score ≥4 benefited from the addition of tirofiban to heparin [4].
●In TIMI 11B and ESSENCE, enoxaparin was associated with better 14-day and six-week post-discharge outcomes compared to unfractionated heparin; these benefits were primarily seen in high-risk patients with risk scores ≥4 and ≥5, respectively [3,6].
TIMI risk index — The TIMI risk index (TRI) is a simpler model derived from the InTIME-II trial of fibrinolytic therapy for ST elevation MI. It can be used simultaneously with the TIMI risk score. (See "Risk stratification after acute ST-elevation myocardial infarction", section on 'TIMI risk index'.)
The TRI is calculated from the following equation, using data obtained at presentation (table 1) [10]:
TRI = (Heart rate x [age/10] squared) ÷ systolic pressure
When applied to over 337,000 patients with non-ST elevation MI in the National Registry of Myocardial Infarction (NRMI) in the United States, there was a graded relationship to in-hospital mortality, ranging from 1.0 to 34.4 percent from the lowest (0 to <10) to the highest scores (≥80) [11]. Patients with a TRI <30 were at low risk. Patients with higher risk indices were more often Killip class >1 and had more frequent comorbidities such as heart failure, renal failure, and chronic obstructive pulmonary disease.
GRACE risk model — The GRACE risk model (and score) discussed below is uncommonly used by our contributors. The model was developed prior to the validation of high-sensitivity (hs) troponin as a reliable single prognostic variable, and it does not appear to add any significant prognostic information to hs troponin.
The TIMI risk score, while extensively validated as described above, is derived from two clinical trial databases. The GRACE registry, a global registry of ACS patients from 94 hospitals in 14 countries, developed two models to estimate the risk of in-hospital and six-month mortality among all patients with an ACS, an end point different from the composite end point in the TIMI risk score.
The in-hospital GRACE model (table 2) was based upon data from 11,389 patients with either an STEMI or an NSTEACS [12]. This model was then validated based upon data from an additional 3972 patients from GRACE and 12,142 patients from the GUSTO IIb trial. Eight independent risk factors were found to account for almost 90 percent of the prognostic information:
●Age
●Killip class (see "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes", section on 'Killip class')
●Systolic blood pressure
●Presence of ST segment deviation
●Cardiac arrest during presentation
●Serum creatinine concentration
●Presence of elevated serum cardiac biomarkers
●Heart rate
Point scores were assigned for each predictive factor and are added together to arrive at an estimate of the risk of in-hospital mortality. A nomogram was published with the GRACE risk model to allow calculation of the risk score. Software is available at http://www.outcomes-umassmed.org/grace/acs_risk/acs_risk_content.html to enable calculation of the GRACE risk score (calculator 2).
Although designed to assess the risk of in-hospital mortality, this GRACE risk model also predicts mortality or recurrent MI at six months and at one year. Its predictive value at one year is slightly greater than that for the TIMI risk score [13,14].
The six-month mortality GRACE model was based upon data from 15,007 patients and validated in a cohort of 7638 patients, all in the GRACE registry [15]. The variables incorporated into this model include age, prior history of heart failure, prior history of myocardial infarction, resting heart rate, systolic blood pressure, ST-segment depression, initial serum creatinine concentration, elevated serum cardiac biomarkers, and performance of in-hospital PCI. The six-month mortality risk based upon this model can be calculated using the website www.outcomes-umassmed.org/grace/.
To improve the usability of the score, the GRACE investigators developed the GRACE risk score 2.0 and electronic tools to assist with the calculation (https://www.outcomes-umassmed.org/grace/acs_risk2/index.html) [16]. The score provides prognosis at six months, one year, and three years and was developed in over 30,000 patients with ACS and validated externally in a registry of nearly 3000 patients. Significant nonlinear associations were found for age, systolic blood pressure, pulse, and creatinine. Overall, clinicians should find it easier to use the Grace Score 2.0 and recommend its use compared to prior iterations.
CRUSADE long-term mortality risk score — Using the CRUSADE registry, over 43,000 patients ≥65 years were used to develop a long-term mortality risk score [17]. The model includes 13 variables and shows good discrimination in the derivation and validation samples.
ACTION registry score — The Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry was used to develop a risk score to predict in-hospital mortality following STEMI and NSTEMI [18]. Multivariable analyses of data from 243,440 patients showed that greater heart rate, lower systolic blood pressure, life-threatening presentations (cardiac arrest, cardiogenic shock, or heart failure), STEMI at presentation, lower creatinine clearance, and higher troponin values were associated with death during the hospitalization. The C statistic was very good at 0.88.
The ACTION score is likely to be most helpful for persons with moderate to severe disease and reflects more contemporary experience than TIMI or GRACE.
USING THE RESULTS OF EARLY RISK STRATIFICATION — Patients at high risk as determined by the use of the risk scores discussed above are usually referred for angiography, if it has not already been performed. For intermediate and low-risk patients who do not undergo early angiography, noninvasive testing prior to discharge may provide information that leads to a decision to perform angiography.
LATE RISK STRATIFICATION — Late risk stratification, performed three to seven days after the event, helps in determining long-term management and prognosis. The importance of risk stratification prior to discharge is illustrated by the observation that, among all major cardiac events that occur in the first six weeks, approximately one-fourth occur after discharge [6].
The main components are measurement of the left ventricular ejection fraction and, primarily in medically managed patients, stress testing to detect possible residual ischemia. The potential use of continuous ST-segment monitoring is also discussed.
Absence of significant coronary disease — In different clinical trials, as well as in the CRUSADE registry, 9 to 14 percent of patients with a non-ST elevation acute coronary syndrome (NSTEACS) who undergo early angiography have no significant coronary stenosis [8,19-22]. Approximately one-half of these patients have no coronary stenosis and one-half have a noncritical (less than 50 to 60 percent) coronary stenosis [19-21]. (See "Acute coronary syndrome: Terminology and classification", section on 'Absence of significant coronary disease'.)
Such patients have a much better short-term prognosis than those with a critical culprit lesion. In a report from the PURSUIT trial, for example, the patients with no or mild coronary disease had a much lower rate of death or nonfatal myocardial infarction (MI) at 30 days than those with significant disease (2 and 6 versus 17 percent) [20]. Similar findings were noted in a report from the CRUSADE registry [22]. Among patients with a non-ST elevation myocardial infarction (NSTEMI), the in-hospital death rate was significantly lower in the patients without significant coronary disease (0.65 versus 2.36 percent for those with coronary disease).
Outcomes at one year in patients with normal or mild disease were provided in an analysis of 7656 patients pooled from three TIMI trials, which looked at a composite primary end point of death, MI, unstable angina requiring hospitalization, revascularization, or stroke [19]. Among the 710 (9 percent) patients with nonobstructive coronary artery disease, a primary end point occurred in 12 percent, including an event rate of 2 percent for death and MI.
Left ventricular function — Assessment of resting left ventricular function is an important part of risk stratification in patients with an NSTEACS and is recommended in all patients [1,23]. Patients with left ventricular systolic dysfunction have increased mortality at long-term follow-up and more than a 50 percent probability of having multivessel coronary disease [24].
In the absence of a specific indication (eg, heart failure or suspected mechanical complication), the left ventricular ejection fraction (LVEF) is usually measured before discharge. However, early measurements may be misleading, since improvement in LVEF, beginning within three days and largely complete by 14 days, is common in patients who either reperfuse spontaneously or undergo percutaneous coronary intervention (PCI), a presumed reflection, at least in part, of recovery from myocardial stunning [25]. (See "Clinical syndromes of stunned or hibernating myocardium", section on 'Acute myocardial infarction'.)
Multiple imaging techniques for assessing left ventricular function are available and each has equivalent prognostic value in the post-MI patient. In general, echocardiography should be used for routine assessment of LVEF after an NSTEACS. Among patients who have had a non-ST elevation myocardial infarction (NSTEMI), it has the added advantage of detecting other factors that can be associated with a worse prognosis such as diastolic dysfunction, concurrent right ventricular dysfunction, increased left atrial volume, mitral regurgitation, and a high wall motion score index, which reflects a more severe impairment in overall left ventricular systolic function [26-31]. (See "Role of echocardiography in acute myocardial infarction", section on 'Left ventricular systolic function' and "Role of echocardiography in acute myocardial infarction", section on 'Left ventricular diastolic function' and "Management and prognosis of chronic secondary mitral regurgitation".)
Stress testing — Stress testing, usually with exercise, can be used to detect residual ischemia and to assess the exercise capacity needed for the cardiac rehabilitation exercise prescription. (See "Exercise ECG testing: Performing the test and interpreting the ECG results".)
The primary role of stress testing is to distinguish between higher-risk subjects with severe and/or extensive ischemia who would have improved outcomes with revascularization, and lower-risk subjects with no or limited ischemia who would have comparable outcomes with medical therapy alone. Pre-discharge stress testing is generally not performed in patients who have undergone PCI or coronary artery bypass graft surgery (CABG) and have been fully revascularized (eg, single vessel disease and successful PCI).
Stress testing for risk stratification in patients with recent NSTEACS is discussed in detail separately. (See "Stress testing in pre-discharge risk stratification of patients with non-ST elevation acute coronary syndrome".)
Continuous electrocardiography — Silent ischemia detected on continuous electrocardiography (continuous ST-segment monitoring) is associated with an increased short-term risk of cardiovascular events. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes", section on 'Silent ischemia'.)
Similar findings have been noted at longer-term follow-up [32,33]. In the MERLIN-TIMI 36 trial, which compared ranolazine to placebo in patients with NSTEMI, 6355 patients underwent an average of six days of uninterrupted 2-lead (Holter) monitoring [33]. (See "New therapies for angina pectoris", section on 'Acute coronary syndrome'.)
One or more transient ischemic episodes were noted in 20 percent of patients. After a median follow-up of almost one year, the patients with transient ischemic episodes had significant increases in the risk of cardiovascular death (7.7 versus 2.7 percent), MI (9.4 versus 5.0 percent), and recurrent ischemia (17.5 versus 12.3 percent). The association between transient ischemic episodes and symptomatic ischemia was not assessed.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)".)
SUMMARY AND RECOMMENDATIONS
●All patients with non-ST elevation acute coronary syndrome should undergo early risk stratification as soon as possible after the diagnosis is secured. The results of risk stratification are used to help choose between immediate coronary angiography, an early invasive strategy, or a conservative approach. (See 'Early risk stratification tools' above.)
●For early risk stratification, we prefer either the GRACE risk model or the TIMI risk score. (See 'TIMI risk score' above and 'GRACE risk model' above.)
●Prior to discharge, patients who have been medically treated and those who have received incomplete revascularization should undergo noninvasive assessment for residual inducible ischemia. (See 'Stress testing' above.)
In the absence of a specific indication (eg, heart failure or suspected mechanical complication), the left ventricular ejection fraction is usually measured before discharge and echocardiography is often the preferred method. If revascularization has been performed, some experts are comfortable waiting until after discharge to obtain an assessment of left ventricular function. (See 'Left ventricular function' above.)
