Introduction
Acute myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide (see Chapter 2 ). Although an estimated 157,000 patients will die each year in the United States as a result of an MI, this statistic belies the wide variability in the rate of mortality and recurrent ischemic events across the spectrum of patients with MI. Although patients presenting with ST-elevation MI (STEMI) are at higher risk for short-term mortality, patients with non–ST-elevation MI (NSTEMI) are at higher long-term risk, which is believed to be related to older age and comorbid medical conditions.
Risk stratification is an integral component of the management of patients presenting with acute MI. Prognostic information is important for appropriate triage and resource allocation to provide the appropriate intensity and location of care for MI patients. Patients and their families, when confronted with an acute MI, expect information about its severity and anticipated consequences. Although treatment for patients with STEMI is directed toward timely reperfusion of the occluded vessel with primary percutaneous coronary intervention (PCI) or fibrinolysis, accurate risk stratification is integral in providing appropriate monitoring and care after reperfusion is achieved (see Chapter 14 ). Moreover among patients with NSTEMI, risk stratification provides not only important prognostic information, but is also critical in deciding the most appropriate care pathway (see Chapter 16 ). Patients at high risk may be more likely to benefit from an early invasive strategy and timely revascularization, whereas an ischemia-driven strategy may be more appropriate for lower risk patients. In addition, many treatment options for patients with acute MI, including revascularization, dual antiplatelet therapy, glycoprotein IIb/IIIa inhibitors, or other anticoagulants, may carry significant bleeding risks. Risk stratification allows clinicians to weigh the benefits and risks of specific therapies when delineating a treatment plan, with the recognition that many (but not all) of the characteristics that portend increased ischemic risk are also contributors to bleeding risk.
Individualized risk assessment for acute MI involves the integration of multiple data points that are available at first medical contact and initially is composed of baseline demographic and clinical characteristics. Upon presentation, additional information gleaned during the initial evaluation, including physical examination findings, the electrocardiogram (ECG), and biomarkers of cardiomyocyte necrosis, is integrated. These data may then be combined into a validated risk model, such as the GRACE (Global Registry of Acute Coronary Events) Risk Score or the TIMI (Thrombolysis In Myocardial Infarction) Risk Score, to provide clear prognostic guidance on short- and long-term risks of death or major adverse cardiovascular events. Such risk scores may be combined with the measurement of additional biomarkers to provide incremental discrimination and potentially reclassify patients more accurately (see Chapter 8 ). Risk evolves in a dynamic way throughout the clinical course based on the therapies delivered, and risk assessment at discharge allows stratification of the likelihood of recurrent ischemic events, sudden cardiac death, and hospital readmission.
In this chapter, we provide an in-depth perspective on clinical risk prediction in acute MI. We begin with demographic and clinical risk factors and then incorporate information on the acute presentation, including symptoms, the physical examination, and the ECG. We then review the development, validation, and use of comprehensive, integrated risk models in clinical use, such as the GRACE Risk Score and the TIMI Risk Scores for STEMI and unstable angina (UA)-NSTEMI. We also discuss the value of ancillary novel biomarkers in conjunction with the integrated risk scores (see also Chapter 8 ). Finally, we describe the importance of postdischarge risk stratification for patients with acute MI.
Demographic and Clinical Risk Predictors
Age
The incidence and prevalence of acute MI increases with each decade of age; the average age of the first MI is approximately 65 years in men and 72 years among women. Older patients are at increased risk of adverse outcomes after an acute MI ( Figure 11-1 ). In the derivation population of the TIMI Risk Score for STEMI (median age 62 years; interquartile range 52 to 70), the univariate odds of mortality were increased almost fivefold among patients older than 65 years (odds ratio [OR], 4.9; 95% confidence interval [CI], 4.2 to 5.7). In a substudy of STEMI patients from the GUSTO-IIb study, each decade of age increased the odds of death or MI by 1.32 (95% CI, 1.04 to 1.76). From most datasets, age is the most important determinant of short-term adverse outcomes across the spectrum of acute coronary syndrome (ACS), although it is more pronounced among patients with acute MI than UA.
There are a number of reasons older patients may have worse outcomes following acute MI. First, older patients have more comorbid conditions, including renal dysfunction, and have a significant burden of multiple medications compared with younger patients. Older patients are more likely to present with atypical symptoms, but they are less likely to have diagnostic ECGs. Older patients are also less likely to receive guideline-recommended medical therapy and to undergo revascularization. Older patients are at significantly increased risk of bleeding, which may be further compounded by inappropriate dosing of antithrombotic medications. Although there is benefit of revascularization for older patients—a benefit that in the population included in clinical trials may be even greater than for younger patients—the benefits of an early invasive strategy have to be balanced against bleeding risk. From the Treat Angina With Aggrastat and Determine the Cost of Therapy With an Invasive or Conservative Strategy (TACTICS)-TIMI 18 study, older patients experienced a greater absolute benefit of early invasive management, with lower rates short- and medium-term cardiovascular ischemic outcomes at the cost of an increased rate of major bleeding. In a patient-level meta-analysis of the Fast Revascularisation during InStability in Coronary artery disease (FRISC-II), Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS), and Randomized Intervention Trial of unstable Angina (RITA-III) trials, the incidence of adverse cardiovascular outcomes at 5 years was significantly lower among patients ages 65 to 74 years (hazard ratio [HR], 0.72; 95% CI, 0.58 to 0.90) and 75 years or older (HR, 0.71; 95% CI, 0.55 to 0.91) who underwent a routine invasive strategy compared with conservative management.
Because of the importance of age in risk stratification among patients presenting with acute MI, it is incorporated in most common risk prediction tools. Despite the evidence that age is the most impactful single predictor of risk, the importance of age tends to be underappreciated by clinicians in their gestalt assessment of risk, a fact that underscores the importance of using objective tools to assess risk.
Sex
Previous studies demonstrated that compared with men, women have a higher burden of comorbid conditions, more often have atypical chest symptoms, present later after symptom onset, and are more likely to be inappropriately discharged from the emergency department. From the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Registry, women more frequently had traditional risk factors but were less likely to receive evidence-based therapies during the hospitalization and at discharge. Although women are at higher unadjusted risk for death and adverse cardiovascular outcomes, this higher risk is largely explained by differences in the underlying risk factors, such as age, comorbidities, and treatment. In a pooled analysis of 11 randomized clinical trials that included 136,247 patients (28% women), women had significantly higher odds of in-hospital mortality (OR, 1.91; 95% CI, 1.83 to 2.00), although this relationship was not significant after multivariable adjustment (adjusted OR, 1.06; 95% CI, 0.99 to 1.15). In a meta-analysis of eight randomized trials, an invasive strategy was preferred among women with high-risk features (OR, 0.67; 95% CI, 0.50 to 0.88), but the point estimate favored harm among low-risk women (OR, 1.35; 95% CI, 0.78 to 2.35); therefore, guidelines support a conservative approach for low-risk women.
Diabetes
According to data from the National Health and Nutrition Examination Survey, diabetes mellitus (DM) affects approximately 28.2 million American adults. Across the spectrum of atherosclerosis and ischemic heart disease, DM is an established potent risk factor for increased mortality, stroke, and coronary artery disease. Patients with diabetes are less likely to present with typical symptoms suggestive of ischemia and more likely to have a delay to presentation. Patients with diabetes are also significantly more likely to have other cardiovascular risk factors, including hypertension and hypercholesterolemia.
Approximately 25% of patients in the GRACE Registry had diabetes and had higher rates of heart failure, renal failure, cardiogenic shock, and in-hospital mortality than patients without diabetes across the spectrum of ACS. In a Finnish population-based study, the risk of first MI in a patient with diabetes was similar to the risk of recurrent MI in a patient without diabetes. From a pooled analysis of 62,036 patients (n = 46,577 with STEMI and n = 15,459 with UA-NSTEMI) from 11 TIMI trials, there was an approximate doubling of 30-day mortality among patients with diabetes compared with patients without diabetes in both UA-NSTEMI (2.1% vs 1.1%; P <.001; OR, 1.78; 95% CI, 1.24 to 2.56) and STEMI (8.5% vs. 5.4%; P <.001; OR, 1.40; 95% CI, 1.24 to 1.57) ( Figure 11-2 ), and subsequent analyses of many clinical trials have consistently demonstrated substantially increased risk of death and adverse cardiovascular outcomes among patients with diabetes. Although patients with diabetes are at higher risk of bleeding and other complications following PCI, an early invasive strategy has been associated with improved outcomes in this patient group. In addition, diabetes is a risk feature that seems to identify a population of patients with multivessel disease who derive particular benefit from coronary artery bypass surgery.
Renal Disease
Patients with chronic kidney disease are at increased risk for adverse cardiovascular outcomes and bleeding ( Figure 11-3 ). In an analysis of 1.2 million patients, Go and colleagues noted a stepwise, graded increase in death and cardiovascular outcomes among patients with worsening renal function, with an almost sixfold increase in adjusted all-cause mortality (adjusted HR, 5.9; 95% CI, 5.4 to 6.5) and a threefold increased risk of any cardiovascular event (adjusted HR, 3.4; 95% CI, 3.1 to 3.8). In an analysis of the VALIANT (Valsartan in Acute Myocardial Infarction Trial) study, even mild renal insufficiency was associated with a 10% increase in the risk of death and adverse cardiovascular outcomes for each 10 mL/min/1.73 m 2 reduction in the estimated glomerular filtration rate less than 81.0 mL/min/1.73 m 2 . Worsening renal disease (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ) remained an independent predictor of increased cardiovascular mortality in the A to Z Trial, even after adjustment for inflammation with C-reactive protein (CRP) (HR, 1.82; 95% CI, 1.1 to 2.97).
Assessment of renal function is critical in initial risk stratification, because patients with renal disease are not only at increased risk of bleeding, but also may develop worsening renal dysfunction because of acute kidney injury following an invasive strategy. Worsening renal dysfunction after cardiac catheterization may be the result of direct renal injury from iodinated contrast, atheroemboli from aortic plaque, or both. Patients presenting with NSTEMI with renal dysfunction may be less likely to undergo an invasive strategy despite the benefit among patients with mild to moderate renal dysfunction. Although providers routinely use either the Modification of Diet and Renal Disease or the Cockcroft-Gault methods to calculate estimated renal function, the Cockcroft-Gault method may be better in predicting mortality following acute MI, particularly among women, small patients (body mass index <25 kg/m 2 ), or the elderly.
Smoking
Although smoking is a traditional cardiovascular risk factor and the cause of an estimated 467,000 deaths annually in the United States, a “smoker’s paradox,” in which smokers presenting with acute MI have better outcomes than nonsmokers, was first described in 1993 among patients presenting with STEMI who received fibrinolytic therapy. However, smokers were approximately 9 years younger than nonsmokers, and subsequent studies have attributed almost all of the improved outcomes among smokers to their younger age and the presence of fewer comorbidities, such as these patients presenting with MI at a younger age when they are better able to survive. In addition, the study that initially described the smoker’s paradox focused on patients who underwent fibrinolytic therapy; subsequent studies that have evaluated patients who underwent invasive management have been conflicting. In an analysis of NSTE-ACS patients from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, Robertson and colleagues reported similar short-term outcomes but worse 1-year outcomes among smokers; in addition, they noted that smokers and nonsmokers had similar anatomic extent of coronary artery disease, despite the fact that smokers were almost a decade younger than nonsmokers. A subsequent analysis from the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial also described worse clinical outcomes at 5 years among smokers.
Peripheral Artery Disease
The presence of peripheral artery disease (PAD) is also an established a marker of increased risk of adverse cardiovascular outcomes among patients presenting with acute MI. Among patients with ACS enrolled in the Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndrome (OPUS)-TIMI 16 Study, patients with PAD were at higher risk of mortality (8.8% vs. 3.9%; adjusted HR, 1.39; 95% CI, 1.07 to 1.81) compared with patients without PAD. From the CRUSADE Registry, Bhatt and colleagues observed an increasing odds of in-hospital ischemic outcomes with disease in multiple vascular beds (OR, 1.31 in patients with disease in three vascular beds; P <.001), whereas Subherwal and colleagues described increased risk of long-term mortality among patients with extensive disease (adjusted HR, 1.49; 95% CI, 1.38 to 1.61) ( Figure 11-4 ). The presence of PAD remained an independent predictor of in-hospital mortality among acute MI patients who underwent PCI (OR, 2.2; 95% CI, 1.7 to 3.0).
Previous Aspirin Use
Although aspirin has been the cornerstone of medical therapy during and following acute MI, previous studies have demonstrated worse outcomes among patients taking aspirin before the event, and previous aspirin use is included as an independent predictor in the TIMI Risk Score for UA-NSTEMI. Although the underlying pathophysiology for this phenomenon is unclear, the relationship may reflect a heighted risk associated with “failure” of therapy with aspirin or the presence of more severe disease in patients who were previously prescribed aspirin.
Initial Presentation
Quality of Angina
The nature, quality, and duration of chest discomfort are known to have prognostic implications, with typical anginal symptoms, defined by Braunwald and colleagues as (1) substernal chest discomfort with a characteristic quality and duration that is (2) provoked by exertion or emotional stress, and (3) relieved by rest or nitroglycerin, conferring worse prognosis than atypical or noncardiac chest pain. The presence of severe angina symptoms, defined as two or more anginal episodes in the previous 24 hours, was incorporated into the TIMI Risk Score for UA-NSTEMI (see the section on Integrated Risk Models for Early Risk Assessment ). Types of discomfort not characteristic of acute myocardial ischemia include extremely brief episodes of discomfort (less than a few seconds), pleuritic pain, middle and/or lower abdominal pain, localized pain (especially at the left ventricular apex or costochondral junction), pain reproduced with palpation or movement, or pain radiating to the lower extremities. However, atypical chest discomfort does not necessarily exclude the possibility of acute MI, because a significant proportion of patients in an older series with acute MI presented with atypical symptoms, including pleuritic pain and/or pain reproducible by palpation. In addition, improvement with either nitroglycerin or a gastrointestinal cocktail does not necessarily include or exclude acute MI.
Hemodynamic Instability
A thorough physical examination, beginning with measurement of vital signs, may be helpful in eliciting signs of heart failure or cardiogenic shock, either as a result of severe left ventricular dysfunction or a mechanical complication of acute MI, such as chordal rupture of the mitral valve apparatus or ventricular wall rupture (see Chapter 25 ). Findings of tachycardia, hypotension, rales, a third heart sound, or a mitral regurgitation murmur are associated with a higher risk of adverse outcomes following MI. The Killip classification, first described in 1967, relied on physical examination findings only and demonstrated increased mortality with escalating signs of heart failure. Although initially described among patients with STEMI, the Killip classification was validated in a pooled analysis of 26,090 NSTEMI patients, with patients presenting with Killip class III/IV at a significantly increased risk of 30-day (HR, 2.35; 95% CI, 1.69 to 3.26) and 6-month mortality (HR, 2.12; 95% CI, 1.63 to 2.75). Because of the importance of these physical examination findings, Killip class was incorporated into the TIMI Risk Score for STEMI and the GRACE Risk Score. Heart rate and blood pressure in and of themselves contain important prognostic information, such that higher heart rate and lower blood pressure at presentation are important risk predictors.
Electrocardiogram
The ECG is a critical component in both risk stratification and management in patients presenting with acute MI. Current guidelines recommend that an ECG be performed within 10 minutes of presentation for all patients with chest pain concerning for acute ischemia. Patients presenting with acute ST-segment elevation are directed along a rapid reperfusion pathway (see Chapter 13 ). Among patients without ST-segment elevation, even relatively minor ST-segment deviations have been correlated with adverse outcomes. Patients with ST-segment depression of even 0.05 mV (0.5 mm on a standard ECG) had higher rates of death or MI compared with patients with T-wave inversions only, even after multivariable adjustment ( Figure 11-5 ). In addition, the degree of ST-segment deviation is also predictive of adverse outcomes. In an analysis of 7800 NSTE-ACS patients from the GUSTO-IV trial, ST-segment deviation of ≥0.2 mV was a stronger predictor of short- and long-term mortality than any other clinical factor or biomarker. Among patients with NSTE-ACS, there was an association between in-hospital revascularization and lower 4-year mortality, especially among patients with ST-segment depression of ≥0.1 mV on the presenting ECG.
Symmetrical T-wave inversions of ≥0.2 mV may be indicative of proximal left anterior descending ischemia; however, nonspecific T-wave inversions less than 0.2 mV may not be helpful from a clinical perspective. It is also important to note that a normal ECG does not exclude acute MI in patients with concerning symptoms, because 2% to 6% of patients presenting with acute MI may have an initially normal or nonspecific ECG; however, patients with acute MI presenting with a normal or nonspecific ECG appear to have lower rates of in-hospital mortality than those with a diagnostic ECG.
Although most studies have evaluated use of the presentation ECG in risk assessment and treatment pathway, Carmo and colleagues evaluated the utility of 24-hour continuous ECG monitoring in 234 NSTE-ACS patients and reported limited incremental prognostic information, especially compared with the GRACE Risk Score. Scirica and colleagues studied the use of 7-day continuous ECG monitoring, and among 6355 patients enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 Trial, they found that patients with one episode or more of ischemia (defined as ≥0.1 mV of ST-segment depression lasting ≥1 minute with a heart rate at the onset of the episode <100 beats/min) had an increased risk of adverse cardiovascular outcomes, even after multivariable adjustment (risk of death: 7.7% vs 2.7%; P <.001; adjusted HR, 2.46; 95% CI, 1.81 to 3.33).
Markers of Cardiomyocyte Necrosis
Evidence of myocardial necrosis in the presence of symptoms concerning for acute ischemia is central to the diagnosis of acute MI. Although less specific markers of myocyte necrosis, including myoglobin, creatine kinase, and creatine kinase-myocardial band fraction, were used in previous decades, cardiac troponin measurements, both the I and T isoforms, are now the most sensitive and specific measures of myocyte necrosis (see Chapter 7 ) and have redefined the UA-NSTEMI spectrum of ACS (see Chapter 1 ).
Biomarkers of necrosis consistently identify a graded relationship with the risk of death after presentation with MI. Importantly, the risk of recurrent ischemia and infarction is shown as an inverted U-shaped pattern, with highest risk in those with low to intermediate increases in biomarkers of necrosis. This presumably identifies patients with high-risk ACS in whom the culprit territory remains at risk. In the TIMI IIIB Trial, Antman and colleagues demonstrated a 1.8- to 7.8-fold increased mortality risk among patients with elevated cardiac troponin I, concordant with similar findings from the GUSTO IIA Trial.
Since these landmark publications, in more than 30 studies, including both clinical trials and community-based cohorts, cardiac troponin has independently predicted the risk of death and recurrent ischemic events among patients with ACS. In aggregate, patients presenting with suspected NSTE-ACS and an elevated concentration of troponin are at an approximately fourfold higher risk of death or recurrent infarction. In patients with STEMI, an elevated concentration of troponin at presentation is also associated with higher short-term mortality. This prognostic information obtained from measurement of cardiac troponin is complementary to the important clinical indicators of risk identified in this chapter, including patient age, ST deviation, and presence of heart failure.
With the development of high-sensitivity assays for cardiac troponin, it is possible to measure low concentrations of troponin and to characterize troponin distribution in healthy populations with greater precision (see Chapter 7 ). In this context, the recommended clinical decision limits have moved toward lower concentrations, raising questions regarding the clinical relevance of low or very low levels of troponin elevation. There are now multiple studies that have validated the heightened risk of patients with positive troponin results using high-sensitivity assays. As an example, in a study of more than 4600 patients, a high-sensitivity troponin assay identified patients at significantly higher 30-day risk of cardiovascular death or new MI using the guideline-based 99th percentile decision limit. Importantly, the study identified a gradient of risk at the low end of concentration that was not reliably measured with previous generations of the same assay. Conversely, a troponin concentration less than the 99th percentile cut point identified a cohort of patients with a clinical diagnosis of NSTE-ACS who were at low risk for death or recurrent ischemic events over 30 days.
Integrated Risk Models for Early Risk Assessment
GRACE Risk Score
The risk score for predicted in-hospital mortality from the GRACE trial remains one of the best validated and most widely used risk scores for early assessment of in-hospital predicted mortality risk. The score was initially developed in an unselected cohort of 11,389 patients (including 509 in-hospital deaths) who presented with ACS in 94 hospitals in 14 geographically diverse countries (Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, New Zealand, Poland, Spain, the United Kingdom, and the United States) from 1999 to 2001.
The initial model was developed using a multivariable logistic regression modeling technique in which a logistic regression model was used to examine the relationship between candidate variables (selected from clinical variables, expert opinion, and previous model results); a multivariable stepwise logistic regression was used to estimate in-hospital mortality. Eight independent risk factors accounted for almost 90% of the prognostic information and were the components of the final model: age (OR, 1.7 per decade; 95% CI, 1.55 to 1.85); Killip class (OR, 2.0 per class; 95% CI, 1.81 to 2.29); systolic blood pressure (OR, 1.4 per 20-mm Hg decrease; 95% CI, 1.27 to 1.45); ST-segment deviation (OR, 2.4; 95% CI, 1.90 to 3.00); cardiac arrest during presentation (OR, 4.3; 95% CI, 2.80 to 6.72); serum creatinine level at presentation (OR, 1.2 per 1 mg/dL increase; 95% CI, 1.15 to 1.35); positive cardiac biomarkers at presentation (OR, 1.6; 95% CI, 1.32 to 2.00); and heart rate (OR, 1.3 per 30 beats/min increase; 95% CI 1.16 to 1.48). An updated version of the risk score (found at http://www.gracescore.org ) allows its use when Killip class and serum creatine are not available, and provides estimates of in-hospital, 6-month, 1- and 3-year death, and 1-year death or MI.
The final model displayed excellent discrimination ability with a c-statistic of 0.83 in the derivation cohort. Of note, univariable predictors of in-hospital mortality that were not found to be statistically significant in the multivariable model included sex, history of heart failure, and history of renal insufficiency. In addition, previous aspirin use (OR, 0.73; 95% CI, 0.58 to 0.91) and previous statin use (OR, 0.50; 95% CI, 0.34 to 0.97) were found to be significant in the multivariable model, but they only added marginally to the overall discriminatory ability (c-statistic = 0.85), and therefore, were not included in the final, simplified model ( Figure 11-6 ).
