Introduction
There has been a major decline in the incidence of myocardial infarction (MI) in the developed world, with the proportion of ST-elevation MI (STEMI) decreasing and the proportion of non–ST-elevation MI (NSTEMI) increasing (see Chapter 2 ). As survival following MI improves, more survivors are candidates for recurrent events, including recurrent MI. However, the incidence of recurrent MI in the community has fallen, with a similar magnitude as the decline in incident MI. In addition to improvements in secondary preventive pharmacotherapy, the shift toward invasive evaluation and management of the initial MI has contributed to this reduction in subsequent recurrent ischemic events. For example, in patients with STEMI, recurrent MI is less frequent after primary percutaneous coronary intervention (pPCI) (see Chapter 17 ) than after fibrinolysis, with in-hospital rates being approximately 2.0% versus 4.0%; readmission rates with recurrent MI at 1 year are approximately 4.8% and 9.6%, respectively.
Other changes in clinical practice have also affected the epidemiology of recurrent MI, with competing directions. MI event rates are sensitive to changes in MI definitions, and after the introduction of the Universal Definition of MI in 2000, the epidemiology of MI has continued to evolve (see Chapter 1 ). Moreover, the use of biomarkers with increased sensitivity (e.g., high-sensitivity troponin assays) have greatly increased the detection of MI (see Chapter 7 ). Increased use of revascularization will increase the incidence of periprocedural MIs. At the same time, the frequency of recurrent MI may be underestimated because patients dying from recurrent MI may be classified as experiencing sudden death.
Detection of Recurrent Ischemia and Infarction
Recurrent Ischemia Without Infarction
Recurrent ischemia after presentation with an acute coronary syndrome (ACS) portends an unfavorable outcome and has major implications for use of health care resources. Ischemic symptoms at rest carry a worse prognosis than ischemia with exercise. In the thrombolytic era, in the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) IIb fibrinolytic trial, recurrent ischemia occurred in approximately 23% of patients with STEMI and 35% of patients with NSTEMI.
Refractory ischemia, which was defined as symptoms of ischemia for 10 minutes with ST-segment deviation or definite T-wave inversion, and/or new hypotension, pulmonary edema, or cardiac murmur believed to represent myocardial ischemia (despite the use of nitrates and either β-blocker or calcium channel blockers), occurred in approximately 20% of patients with ischemia. Refractory ischemia was associated with an approximate doubling of 30-day mortality among patients with ST-segment elevation (11.8 % vs. 5.4%; P < .001) and an even greater mortality risk among patients without ST-segment elevation (12.0% vs. 2.7%; P < .001).
Most ischemia is silent, and can be detected on 24-hour continuous electrocardiographic (ECG) monitoring. The frequency and duration of silent ischemia has a direct relationship to prognosis. Several studies that used continuous ST-segment monitoring showed that 15% to 30% patients with NSTE-ACS had transient episodes of ST-segment changes. These patients had an increased risk of subsequent cardiac events, including cardiovascular death. ST monitoring has been shown to add independent prognostic information to the ECG, troponins, and other clinical variables.
In the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–TIMI 36) trial, continuous ECG recording was performed for 7 days in 6355 patients with NSTE-ACS; 42% of the patients underwent revascularization during the index hospitalization. Patients with ≥1 episode of ischemia (20%) during the first 7 days were at increased risk of cardiovascular death (7.7% vs. 2.7%; P < .001), MI (9.4% vs. 5.0%; P < .001), and clinically manifested ischemia (17.5% vs. 12.3%; P < .001) over the following year.
With early invasive evaluation and management of MI, the incidence of early recurrent ischemia has decreased substantially. Among patients with STEMI in the PAMI (Primary Angioplasty in Acute Myocardial Infarction) study, recurrent ischemia was significantly less frequent in patients who had reperfusion with pPCI (10.3%) than in those who received fibrinolytic therapy (28.0%). Similarly, a major effect of early invasive management for NSTEMI is the reduction in recurrent ischemic events (see Chapter 16 ).
Because of the adverse prognosis of recurrent ischemia, clinical practice incorporates the performance of serial ECGs, monitoring for recurrent ischemic symptoms, and in some centers, continuous ST-segment monitoring. Many STEMI and NSTEMI patients are discharged 3 to 4 days after they have undergone an invasive strategy with pPCI or a pharmacoinvasive strategy with stenting of the culprit and often nonculprit lesions, either at initial angiography or subsequently. In patients who have typical ischemic pain at rest, a stress test is not necessary to define the need for additional therapy. A test for inducible ischemia may be considered in patients who are not fully revascularized before hospital discharge to help determine whether coronary angiography should be performed and revascularization, as appropriate, should be undertaken (see Chapter 30 ).
Diagnosis of Recurrent Myocardial Infarction
Classification of Recurrent Myocardial Infarction
The criteria for the diagnosis of MI according to the Third Universal Definition of MI are discussed in Chapter 1 and shown in Table 1-2 . MIs are a heterogeneous group of events and are classified by the Universal Definition of MI into five types that differ according to pathophysiology, prognosis, and treatment (Table 1-4) . The diagnosis of the initial MI is discussed in Chapter 1 , Chapter 6 , and Chapter 7 . This section focuses on the diagnosis of recurrent MI as a complication in patients who have presented with an initial MI event.
Spontaneous Myocardial Infarction
Spontaneous MIs (type 1) are the most commonly observed MIs in clinical practice, and they are also the most common type of recurrent MI during the long-term. Clinical judgment is required to distinguish type 2 (supply–demand imbalance) MIs from type 1 MIs by taking into account the contribution of increased myocardial demand and decreased supply and the likely absence of acute plaque rupture based on all of the clinical information available (see Figure 1-3 ).
Myocardial Infarction Related to Percutaneous Coronary Intervention (Type 4a)
Myocardial necrosis associated with PCI is a frequent cause of early recurrent MI and may be caused by several mechanisms, including distal embolization of plaque and/or thrombus with resultant microvascular plugging, occlusion of a side branch or a major coronary artery, coronary dissection, spasm, or endothelial dysfunction. The association between type 4a MI and mortality is controversial and less important than spontaneous MI.
Myocardial Infarction Caused by Stent Thrombosis (Type 4b)
Stent thrombosis after PCI for STEMI and NSTEMI is an infrequent but medically important event because of its adverse prognosis. This risk is higher with drug-eluting stents (DES) than with bare metal stents, and is associated with MI and death. MI may also occur that is unrelated to the stent. The risk of stent thrombosis is less with the new generation DES, and the risk is approximately 50% lower than with the first-generation DES.
Myocardial Infarction with Coronary Artery Bypass Grafting (Myocardial Infarction Type 5)
During coronary artery bypass grafting (CABG), numerous factors can lead to periprocedural myocardial injury with necrosis. These include direct myocardial injury from (1) suture placement or manipulation of the heart, (2) coronary dissection, (3) global or regional ischemia related to inadequate intraoperative cardiac protection, (4) microvascular events related to reperfusion, (5) myocardial injury induced by oxygen free radical generation, or (6) failure to reperfuse areas of the myocardium that are not subtended by graftable vessels. Magnetic resonance imaging studies suggest that most necrosis in this setting is not focal, but diffuse and localized in the subendocardium.
Recurrent Myocardial Infarction and the Electrocardiogram
The ECG diagnosis of suspected recurrent MI following the initial MI may be confounded by the initial evolutionary ECG changes. Recurrent MI should be considered when ST-segment elevation of more than 0.1 mV recurs, or new pathologic Q waves appear, in at least two contiguous leads, particularly when associated with ischemic symptoms for 20 minutes or longer. In the presence of persistent ST-segment elevation (failed resolution of ST-segment elevation because of impaired microvascular flow) early after reperfusion, detection of reinfarction by ECG alone is difficult and requires consideration whether there has been a proportional increase since the preceding ECG, together with clinical symptoms of ischemia. Coronary angiography to detect reocclusion is sometimes necessary in such cases to resolve uncertainty. However, reelevation of the ST-segment can also be seen in threatened myocardial rupture and the presence of a left ventricular aneurysm, and should lead to consideration of these alternatives.
Biomarkers and Recurrent Myocardial Infarction
Because of persistent elevation of biomarkers of necrosis in the first days to weeks after a large initial MI, the diagnosis of recurrent MI can be challenging and is dependent on identifying a dynamic pattern of biomarker values separate from the initial MI, rather than simply elevation above the 99th percentile alone. In patients in whom recurrent MI is suspected from clinical signs or symptoms following the initial MI, an immediate measurement of troponin is recommended. A second sample should be obtained 3 to 6 hours later if the troponin level is elevated, but stable or decreasing at the time of suspected recurrent MI. Recurrent MI can be diagnosed if there is a more than 20% increase of the contemporary troponin value in the second sample. Two troponin values are considered to be analytically different if they are separated by more than 3 SDs of the variance (see Chapter 7 ). For most contemporary non–high-sensitivity troponin assays, the SD is 5% to 7% at the levels involved with recurrent MI. Therefore, a 20% change should be considered significant (i.e., more than 3 SDs than expected from the analytical variability itself). This value should also exceed the 99th percentile upper reference limit (URL). If the initial troponin concentration is normal, the criteria for diagnosing a new acute MI apply (see Chapter 7 ).
Comparison of Different Definitions of Myocardial Infarction
In the OAT (Occluded Artery Trial) study, the OAT definition for the diagnosis of recurrent MI required two of three criteria: symptoms, the ECG, and an elevation of biomarkers. The ECG requirements were new Q waves >0.03 s and/or Q-wave voltage >1⁄3 QRS in >2 related leads on ECG. The biomarker criteria included a ≥2-fold elevation for type 1 MI, a ≥3-fold elevation for type 4a, and a ≥5-fold elevation for type 5 infarction. The 2007 Universal Definition had similar criteria for type 4a and type 5 MI, but this definition had a lower threshold for type 1 MI based on any biomarker elevation above the upper limit of normal (ULN). Consequently, more MIs were detected by the Universal Definition ( Table 23-1 ).
| Type of Re-MIs by Universal Definition | No. of Re-MIs by Universal Definition | No. of Additional Re-MIs Picked Up by Universal Definition |
|---|---|---|
| Type 1: spontaneous | 106 | 9 |
| Type 2: secondary | 7 | 4 |
| Type 3: sudden death | 12 | 10 |
| Type 4a: PCI related | 10 | 4 |
| Type 4b: stent related | 33 | 1 |
| Type 5: CABG related | 1 | 1 |
| Total | 169 | 29 |
In a pooled analysis of two large negative phase III trials with the P2Y 12 antagonist, cangrelor, which used the Universal Definition of MI instead of the protocol definition of MI, there was a significant reduction in the primary endpoint, which included MI as opposed to a null result. This result contributed to further development of cangrelor with a further large phase III trial, the CHAMPION PHOENIX (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition PHOENIX) trial, which used the Universal Definition of MI in the primary endpoint. The trial showed a significant 20% reduction in MI and a significant reduction in the primary endpoint.
Causes and Predictors of Recurrent Myocardial Infarction
Causes of Recurrent Myocardial Infarction
There are a number of causes of recurrent MI related to features of the plaque, features of the blood (thrombogenesis), and features of the patient. Activation of the coagulation system continues for at least 6 months and plays a major role in the occurrence of recurrent MI related to the culprit lesion and at other sites in the coronary tree ( Table 23-2 ). Recurrent MI may also be procedurally related, as described in the preceding section on Classification of Recurrent Myocardial Infarction.
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Predictors of Recurrent Myocardial Infarction
Factors that have been shown to be predictors of recurrent MI are shown in the Table 23-3 . Some are contradictory (e.g., smoking). Other traditional risk factors for coronary artery disease (CAD) (e.g., hypertension, diabetes, dyslipidemia) are also likely to increase the risk for recurrent MI.
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In patients with STEMI enrolled in the GUSTO I and GUSTO III fibrinolytic trials, recurrent MI occurred in 4.3% of patients at a median of 3.8 days after administration of fibrinolytic therapy. Advanced age, shorter time to fibrinolysis, non-U.S. enrollment, nonsmoking status, previous MI or angina, female sex, anterior MI, and lower systolic blood pressure were associated significantly with the occurrence of recurrent MI. In the pooled PAMI trials, predictors of recurrent MI at 30-days were Killip class higher than 1, ejection fraction less than 50%, final coronary stenosis more than 30%, coronary dissection, and presence of thrombus.
Among patients with NSTEMI, in the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, which evaluated patients with NSTEMI and/or unstable angina who were managed medically without planned revascularization, MI was the most common endpoint, representing 45.3% of all first events, which included cardiovascular (CV) death and stroke. A prediction model for a first spontaneous MI event included 17 variables. The strongest predictors of spontaneous MI were older age, NSTEMI versus unstable angina as the index event, diabetes mellitus, no pre-randomization angiography, and higher baseline creatinine values. The prediction model performed well in terms of predictive capabilities (c index = 0.732) and had good calibration, especially in patients with a low-to-moderate risk of spontaneous MI ( Figure 23-1 ).
Characteristics of the culprit lesion on angiography, and in particular, the American College of Cardiology/American Heart Association type C lesions ( Table 23-3 ) have been associated with worse prognosis. Among the 3661 patients who underwent PCI in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) study, patients with type C lesions had higher 30-day rates of mortality (1.2% vs. 0.6%; P = .049), MI (9.2% vs. 6.3%; P = .0006), and unplanned revascularization (4.3% vs. 3.1%; P = .04) compared with those without type C lesions. In multivariable analysis, type C lesions were independently associated with MI (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.04 to 1.80; P = .02) and composite ischemia (OR, 1.49; 95% CI, 1.17 to 1.88; P = .001) at 30 days ( Figure 23-2 ).
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