Framing the clinical need for biomarkers of ischemia

Risk Stratification Among Patients With Nontraumatic Chest Pain

Given the current level of diagnostic uncertainty, risk stratification of every patient with possible ACS has become the foundation of virtually all chest pain evaluation strategies. An effective strategy to reduce the probability of inadvertently discharging a patient with ACS is to admit every patient who presents with chest pain or related symptoms. The correlation between increased admissions and reduced missed AMI rates is well described (Fig. 1) (3). Unfortunately, admitting large numbers of patients unnecessarily is not economically viable and is increasingly difficult to justify in the face of current constraints on hospital bed capacity. Utilization of standardized risk-based strategies that avoid admission for lower-risk patients is now well established as both clinically sound and cost-effective.

Fig. 2. Evaluation ofpatient presenting with chest pain. The initial evaluation of the patient presenting with chest pain, primary risk stratification, is based on differentiating ACS from non-ACS and is done via the history, physical examination, and ECG. The sensitivity for this is high but not perfect. Although a limited number of high-risk AMI patients can be identified by the ECG, it is impossible on this basis alone to correctly identify all ACS patients, or to differentiate unstable angina from MI. Thus, a secondary risk stratification process including biomarkers of myocardial necrosis and imaging techniques is performed to identify the remainder of the higher-risk patients. Ultimately, the results of such testing may either provide a definitive diagnosis or contribute to the ongoing risk assessment process. CAD, coronary artery disease.

Prognostic Tests

Fig. 2. Evaluation ofpatient presenting with chest pain. The initial evaluation of the patient presenting with chest pain, primary risk stratification, is based on differentiating ACS from non-ACS and is done via the history, physical examination, and ECG. The sensitivity for this is high but not perfect. Although a limited number of high-risk AMI patients can be identified by the ECG, it is impossible on this basis alone to correctly identify all ACS patients, or to differentiate unstable angina from MI. Thus, a secondary risk stratification process including biomarkers of myocardial necrosis and imaging techniques is performed to identify the remainder of the higher-risk patients. Ultimately, the results of such testing may either provide a definitive diagnosis or contribute to the ongoing risk assessment process. CAD, coronary artery disease.

The current convention that all chest pain patients must be rapidly evaluated for the probability of an ACS through an initial assessment based on the ECG, history, and physical examination is referred to as "primary risk stratification" (4). ST-segment deviation, either elevation or depression, identifies higher-risk cohorts for whom specific therapies should be initiated and admission to a critical care unit is indicated. Guidelines for the evaluation and treatment ofthese patients have been recently published (5-7). The remaining patients constitute a cohort for whom the probability of ACS is lower, but not absent. Among these "lower-risk" patients, often comprising up to two-thirds of all emergency department (ED) patients undergoing a chest pain evaluation, there is a small group for whom ACS is the cause of their presenting symptoms. Although this incidence of occult ACS is low, failure to identify those few higher-risk patients remains problematic (2). For this reason, a "secondary risk stratification" process must be initiated when the diagnosis is not certain (Fig. 2). This process includes a number of biochemical markers, imaging modalities, and provocative tests.

Chest pain evaluation programs, (e.g., chest pain emergency rooms, clinical diagnostic units), are now in place in many hospitals and incorporate protocols, pathways, and clinical practice guidelines to provide consistency and structure to the evaluation and management ofthe patient with nontraumatic chest pain. Whereas erratic variation in practice contributes to lower quality of care and to higher costs owing to inappropriate utilization of resources (8), a systematic approach can reduce costs for chest pain evaluation through improved efficiency (9,10). This observation has fueled efforts to generate consensus as to the structural, procedural, organizational, and managerial components required for effective chest pain evaluation (11). However, no amount of organizational efficiency can replace the ability to provide the right test needed to guarantee the right diagnosis at the right place and time.

Pathophysiology of ACS

The development of biochemical markers for ACS requires an understanding of the pathophysiology of atherothrombotic coronary artery disease. This condition is chronic and progressive, marked by episodic acute manifestations, including unstable angina and AMI, which are infrequent, but potentially fatal. The precipitating event in ACS is most often disruption of a "vulnerable" atherosclerotic plaque weakened by inflammation, exposing the highly thrombogenic subendothelial components of the atheroma core (12, 13). In many cases, obstruction of the coronary artery by thrombus is minimal, resulting in little or no impairment to coronary flow. Alternatively, the thrombus can result in total occlusion of the artery with classic symptoms and ECG findings. The combination of reduced blood flow and increased oxygen demand precipitates the critical imbalance of oxygen supply and demand that leads to myocardial ischemia (i.e., unstable angina). Persistent ischemia can result in myocyte death, which may be detected using biomarkers of necrosis and forms the basis for the diagnosis of AMI (14). Necrosis is an irreversible terminal event and its presence signifies considerable risk. To prevent necrosis from occurring, one must detect ACS earlier in its course and intervene. Thus, the detection of ischemia provides the optimal opportunity for early diagnosis and intervention in patients with ACS.

Diagnosis of ACS

The diagnosis of ACS is predicated on evidence of the physiological process just described. Although the initial assessment typically occurs with limited data, including only the history, physical examination, and ECG, the sensitivity of this strategy is good, approx 93-95% (15-17). However, unfortunately, the consequences of missed diagnoses are high (16,17), with increased morbidity and mortality (1,18). Failure to make a diagnosis of AMI remains the single highest payout for malpractice litigation against ED physicians (19). Moreover, only approx 20% ofthe malpractice claims for missed MI are against ED physicians, with almost 70% against primary care physicians. In addition to the objective ofreducing the number of missed MIs, optimal care ofthe population with ACS requires rapid identification of those with ischemia prior to the onset of necrosis (20).

The understanding of the pathophysiology of ACS provides a myriad of opportunities for diagnostic and prognostic testing within this pathophysiological construct (Fig. 3). However, assessment at different stages or of different contributors to the genesis of ACS is likely to have different implications for prognosis and therapy. Thus, the evaluation of new tools for diagnostic and prognostic application in ACS should be distinguished along the following lines:

1. Chronicity: A distinction must be made between "disease-state" markers specific to atherosclerosis and "acute event" markers, such as necrosis markers used for the detection of AMI.

2. Timing: The window during which a test may be useful is discrete and varies widely among tests.

Fig. 3. Targets for detection of ACSs. When the components of ACS are considered individually, there are multiple targets for detection at all levels. The two historical standards have been the detection ofischemia via the ECG and the detection of necrosis using biomarkers; the limitations to each are discussed in the text. Plaque disruption and thrombus formation may be such frequent events that their detection may signal a period of elevated risk more so than the actual occurrence of ACS as it is known clinically. Biomarkers for these processes may provide information about risk but are unlikely to be useful for the diagnosis of an acute event if this frequency of occurrence is high. At present, there are no biochemical markers for reduced intracoronary blood flow, so ischemia is the likely target for biomarker development aimed at preventing necrosis. CRP-C, reactive protein; IL-6, interleukin-6; MMP, matrix metalloproteinase; FPA, fibrinopeptide A; TPP, thrombus precursor protein; BNP, B-type nutriuretic peptide; TnI, troponin I; TnT, troponin T.

Fig. 3. Targets for detection of ACSs. When the components of ACS are considered individually, there are multiple targets for detection at all levels. The two historical standards have been the detection ofischemia via the ECG and the detection of necrosis using biomarkers; the limitations to each are discussed in the text. Plaque disruption and thrombus formation may be such frequent events that their detection may signal a period of elevated risk more so than the actual occurrence of ACS as it is known clinically. Biomarkers for these processes may provide information about risk but are unlikely to be useful for the diagnosis of an acute event if this frequency of occurrence is high. At present, there are no biochemical markers for reduced intracoronary blood flow, so ischemia is the likely target for biomarker development aimed at preventing necrosis. CRP-C, reactive protein; IL-6, interleukin-6; MMP, matrix metalloproteinase; FPA, fibrinopeptide A; TPP, thrombus precursor protein; BNP, B-type nutriuretic peptide; TnI, troponin I; TnT, troponin T.

3. Severity: Any test may be influenced by the magnitude of the perturbation being studied.

4. Context: The value of certain tests may be limited to or influenced by the specific situation in which it is being used. Interpretation of any test result must consider the clinical situation in which the test is being performed, and the specific information provided.

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