Clinical use of troponin and other biomarkers in specific patient subsets seen in the emergency department or chest pain unit

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The use of biomarkers is predicated in large part on the underlying nature of the patients being evaluated. The following suggestions are developed predicated on risk stratification.

Patients with ST elevation and myocardial infarction

Patients who present with ST elevation myo-cardial infarction (STEMI) do not need biomarker measurements before the initiation of therapy. Therapy should be started before the return of biomarker data to ensure the most rapid initiation of therapy, which is critical in this setting. Recent data suggests that troponin elevations identify patients at high risk for adverse events. Patients who have elevated troponins have a lower rate of coronary recanalization with thrombolysis [36] or in response to direct percutaneous coronary intervention (PCI) (Fig. 1 ) [37]. The largest part of this effect probably is related to the fact that it takes time for elevations of troponin to develop, and therefore, patients who present with elevated tro-ponin, are patients who present later than those who do not manifest elevations. Time from the onset of symptoms to treatment is the most critical determinant of the success or failure of recanalization and limitation of infarction size, which is likely the largest reason why patients who present with

Fig. 1. Frequency of successful direct PCI when troponin is elevated (cTnI > .4 ng/ml) compared with when it is "normal" (< 0.4ng/ml). From Matetzky S, Sharir T, Domingo M, et al. Elevated troponin I level on admission is associated with adverse outcome of primary angioplasty in acute myocardial infarction. Circulation 2000;102:1611-6; with permission).

Fig. 1. Frequency of successful direct PCI when troponin is elevated (cTnI > .4 ng/ml) compared with when it is "normal" (< 0.4ng/ml). From Matetzky S, Sharir T, Domingo M, et al. Elevated troponin I level on admission is associated with adverse outcome of primary angioplasty in acute myocardial infarction. Circulation 2000;102:1611-6; with permission).

elevated troponins do poorly. In analyses where one attempts to correct for the time from the onset of infarction to presentation, however, a major adverse effect of having an elevated troponin still exists (Fig. 2) [38]. The ability to determine when the onset of symptoms has occurred may be inaccurate or it may be that other pathophysiology exists related to how infarction is initiated, which mediates this effect. Nonetheless, knowing that the tro-ponin is elevated in patients who present with STEMI predicts a lower likelihood of recanaliza-tion, a lower TIMI flow grade with reperfusion [39], and an adverse short- and long-term prognosis. The therapeutic implications of this phenomenon are unclear at this time, but in one study, stenting seemed to have a positive impact [40]. No

Fig. 2. Relationship between the time of onset of symptoms, troponin and mortality. Note at any given time from the onset of symptoms to randomization there is an increased risk associated with an elevated troponin. From Ohman EM, Armstrong PW, White HD, et al. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. GUSTO III Investigators. Global use of strategies to open occluded coronary arteries. Am J Cardiol 1999;84:1281-6; with permission.

Fig. 2. Relationship between the time of onset of symptoms, troponin and mortality. Note at any given time from the onset of symptoms to randomization there is an increased risk associated with an elevated troponin. From Ohman EM, Armstrong PW, White HD, et al. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. GUSTO III Investigators. Global use of strategies to open occluded coronary arteries. Am J Cardiol 1999;84:1281-6; with permission.

data exist about this issue with biomarkers other than troponin.

High-risk patients with acute coronary syndromes

The high-risk patient group that has been well represented in most of the major intervention trials. These patients are often elderly, have had chest discomfort at rest, have transient ST segment changes or bundle branch block, an increase in the tempo of their symptoms or signs, and can have evidence of hemodynamic instability or arrhythmias. This group often has a high frequency of elevated troponins in the range of 50% to 60% [41-44]. If so, they fulfill the definition of non-STEMI per the ESC/ACC [23,24].

In this patient subset, as with STEMI, an elevated troponin often is unnecessary for decisions concerning admission. Information suggests, however, that elevated troponin values define a subset at high risk [41-45] and provide important information with which to guide therapy. Patients who present with elevated troponins have adverse coronary anatomy as assessed angio-graphically with more thrombus, reduced TIMI grades of perfusion, more complex lesions, and more extensive disease (Fig. 3) [46]. Thus, they require and are more apt to benefit from the use of more sophisticated therapies. These patients have fewer ischemic events if treated with low molecular weight heparin rather than unfractionated hep-arin [47]. These studies do not show a mortality benefit. IIB/IIIA agents also have been found to markedly reduce death and recurrent MI in these patients, but, again, the benefit is almost exclusively in the recurrent event category. The effects of IIB/IIIA agents are particularly strong in those patients who undergo percutaneous intervention [48]. Their use, then, is the present standard of care for patients who present with acute coronary syndromes and elevated troponins [49]. Patients who present without elevated troponins do not seem to benefit from the adjunctive use of low molecular weight heparin or IIB/IIIA agents in the setting of acute coronary syndromes. The recent accelerating use of clopidogrel has raised questions about whether the results of these previous studies would be the same if clopidogrel had been used adjunctively. Clopidogrel recapitulates the benefits of IIB/IIIA agents, it could be argued. Alternatively, it is possible that synergism exists between clopidogrel and IIB/IIIA agents and that patients would benefit even more from the combination. Until ongoing trials answer this key question, the standards and guidelines proposed by the American Heart Association/ American Cardiac College would recommend that patients who present with an acute coronary syndrome and an elevated troponin receive IIB/ IIIA agents [49]. In the CURE trial, clopidogrel seemed to benefit patients who presented with and without troponin elevations [50].

As might be expected, because short-term benefit is associated with the use of these agents so is long term benefit [51]. In addition, recent data has substantiated that the use of early invasive therapy, which in the United States means cardiac catheterization within the next 12 to 24 hours and interventional therapy (with stenting and a PCI or coronary artery bypass grafting),

Fig. 3. Angiographic relationships with troponin in patients with acute coronary syndromes. From Scirica BM, Morrow DA. Troponins in acute coronary syndromes. Prog Cardiovasc Dis 2004;47:177-88; with permission.

leads to substantial benefit in patients who present with acute coronary syndromes and elevated troponins [52,53]. This benefit is not generally observed in patients who present without elevations. The one exception recently published is that women who more often present with normal values of troponin but elevated BNP or CRP may, nonetheless, benefit from an early aggressive invasive strategy (Fig. 4) [54]. Unfortunately, the data were based not on serial troponin data but on only the initial sample. Few other data exist at present to substantiate this claim.

Intermediate and low risk for the patient subsets

The intermediate and low-risk subsets of patients are the groups that usually are problematic in the ED or chest pain unit. The intermediate risk group often does not have rest pain or ongoing pain and lacks ECG changes, although this group may have a high pretest probability of having coronary artery disease. In contrast, the low-risk group usually has normal ECGs or only minimal T changes and often may not have impressive risk factors. Nonetheless, because of the need to diagnose as many patients as possible at risk for acute infarction given its morbidity and potential mortality, these patients need to be tri-aged and evaluated aggressively. In addition, this group is where a high percentage of malpractice dollars are lost. For these reasons, a conservative approach often is mandated. The downside of this approach is that it is costly to admit a large number of patients solely because of this concern.

In this setting, troponin markers are again the markers of choice. In a landmark study of 733 consecutive patients who presented with chest discomfort, Hamm and colleagues [55] demonstrated that almost all patients at short-term risk could be identified using troponin (Fig. 5). Several caveats existed that were important in that study. The first caveat was that at least one troponin value needed to have been obtained at least 6 hours after the onset of symptoms to make sure that there had been time for the marker to rise. Unless the onset of symptoms is totally clear, it is wise to start the clock at the time of presentation. A second important caveat was the troponin value used was the limit of detectablity (ie, a highly sensitive standard). Although the assays involved were less sensitive than contemporary assays, the concept probably is still correct. With modern assays, the use of the so-called 10% CV value is advocated [21,25]. When there is a high pretest probability of disease, as in the patients with overt acute coronary syndromes, the data are clear that using the lowest level of troponin detectable, (ie, the 99th percentile), provides greater predictive accuracy [56]. The pretest probability of a given elevation, being a true positive rather than a false positive, is high in the group with severe disease. When one deals with a patient population where the pretest probability of disease is somewhat less, severe disease is less likely. In that

Fig. 4. Outcomes of therapy by gender. Note patients with any positive marker (troponin, BNP or CRP) benefited. Some suggestion of detriment exists in an invasive therapy in patients without an elevations in any marker. From Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy. Circulation 2004;109:580-6; with permission.

Fig. 4. Outcomes of therapy by gender. Note patients with any positive marker (troponin, BNP or CRP) benefited. Some suggestion of detriment exists in an invasive therapy in patients without an elevations in any marker. From Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy. Circulation 2004;109:580-6; with permission.

Fig. 5. Survival of patients evaluated to include or exclude acute myocardial infarction. From Hamm CW, Goldmann BU, Heeschen C, et al. Emergency room triage of patients with acute chest pain by means of rapid testing for TnT or troponin I. N Engl J Med 1997;337:1648-53; with permission.
Fig. 6. Events in patients with various troponin values. Note even what are called in this figure marginal elevations have prognostic significance. From Henrikson CA, Howell EE, Bush DE. et al. Prognostic usefulness of marginal troponin T elevation. Am J Cardiol 2004;93:275-9; with permission.

population, if one uses values where the assays are imprecise, the percentage of false-positive elevations is far greater. For that reason, in this population, it is important to use what is known as the 10% CV value rather than the 99th percentile, which is a level where few, if any, false-positive elevations are caused by imprecision. Most would advocate using the 10% CV level (which is usually close to the 99th percentile) in all patients with the recognition that in patients who are at high risk clinically even lower levels may have a prognostic and therapeutic significance. In the intermediate and lower-risk groups, however, if one uses the lower level (ie, the 99th percentile), an unaccept-ably high percentage of patients is apt to have false positives. The 99th percentile and the 10% CV values for present assays are shown in Table 1 [21]. Caution is advised because the assays themselves and, thus, the values, presented change frequently.

Many of the studies that have been done have used high cutoff values for troponin in evaluating ED patients. Recently, a study from Johns Hopkins [57] evaluated patients who had low levels and patients who had intermediate levels between the 99th percentile and what is known as the ROC determined cutoff value for MI, a level initially used when the assays were novel to match the sensitivity of CK-MB. As with almost every other study that has been done, a substantial short- and long-term adverse prognostic effect was observed with even minor elevations of troponin (Fig. 6). More of these studies are needed, but they were consonant with the vast body of clinical information that suggests the elevated troponin values usually have important prognostic significance.

Intermediate or low-risk patients who present with an elevated troponin may or may not have acute ischemic heart disease. Many etiologies exist for troponin elevations, and many of them may need to be evaluated as part of an evaluation in the ED or chest pain center. Two of the more common ones are pulmonary embolism [58,59] and congestive heart failure [60,61]; these can mimic the presentation of an acute coronary syndrome and both are associated with an adverse prognosis when troponin elevations occur. In general, the troponin elevations observed are modest. Elevations associated with pulmonary embolism resolve rapidly (by 40 hours) [62]. Elevations in patients who present with congestive heart failure persist for a longer period and are found in patients with and without coronary artery disease. Chest pain and elevated troponins in patients may be caused by some of these other etiologies for elevated troponins, but no overt coronary artery disease angiographically were at accentuated risk in the Tactics-TIMI-18 trial [63]. The coronary angiogram may not be, in every instance, totally reliable for the detection of acute coronary artery disease, especially when a delay exists between the onset of symptoms and implementation of the diagnostic procedure. Nonetheless, these data suggest that the due diligence of any good clinician seeing a patient who presents with an elevated troponin in these intermediate and lower-risk groups is not only to determine whether or not the patient is at risk for acute ischemic heart disease. The physician must also make sure that the elevations are not a result of other causes that may require different types of therapy (see later discussion).

Extensive evaluations of low risk patients have not been common. In an important study, however, the group from Galveston [64] evaluated a cohort of over 400 patients who presented with a low-risk history and normal or near normal ECG. They selected their inclusion criteria to be associated with a 5% to 7% incidence of MI. They then evaluated the frequency of coronary artery disease by offering angiography to all those patients with an elevated troponin and enrolling a control group that was selected from similar patients with chest pain but without elevated troponins as a comparison group. In that study, which used a higher tro-ponin than has been advocated by this author, patients who presented with an elevated troponin had a 90% frequency of angiographic coronary artery disease. In two thirds, it was double or triple vessel disease. In addition, during follow up, these individuals had a 33% incidence of ischemic events caused by coronary heart disease (Fig. 7). These data demonstrate the importance of an elevated troponin in patients who present with chest pain, even those at low risk. Had the investigators used a lower cutoff value, the 10% CV value for example, it is possible there may well have been a larger number of patients with increases attributable to diseases other than acute ischemic heart disease. However, it is possible that the frequency of coronary artery disease seen in the control group of 23% would have been substantially diminished. Thus, it seems likely that the use of the low cutoff values may help to identify patients who are at risk when they present with chest discomfort.

No comparable data exist with any other markers in either risk group.

Cardiac death Nonfatal Ml Unstable angina CHF

Any event

Negative cTnT n=368 1 (0-3) 3 (0.8) 40 (11) 3 (0.8) 47 (13)

Cardiac death Nonfatal Ml Unstable angina CHF

Any event

Negative cTnT n=368 1 (0-3) 3 (0.8) 40 (11) 3 (0.8) 47 (13)

0123456789 10 11 12 Months

Pt at risk

PoscTnT 37 32 30 29 28 27 25 21 18 17 15 14 8 Neg cTnT 368 355 353 345 344 343 272 260 250 224 200 183 84

Fig. 7. Prognostic significance of troponin elevations in patients with normal or near normal electrocardiograms. From deFilippi CR, Tocchi M, Parmar RJ, et al. Cardiac troponin T in chest pain unit patients without ischemic electrocardiographic changes: angiographic correlates and long-term clinical outcomes. J Am Coll Cardiol 2000;35:1827-34; with permission.

Patients with renal failure

The most common cause of death in patients who present with renal failure is cardiovascular [65]. Coronary artery disease is common and events tend to occur during the period when patients have a longer interval between dialysis visits [65,66]. In patients who present with acute coronary syndromes, the interpretation of troponin elevations should not be altered by the presence of renal failure [67].

Other dialysis patients at risk who do not have acute coronary syndromes can often also be identified by having an elevated troponin [68,69]. These patients invariably have pathologic evidence of cardiac injury [70]. This group manifests differences in the frequency of elevations of cTnT and cTnI [68]. Many more elevations of cTnT occur than cTnI, and this has led some people to believe that the elevations of cTnT are false positives. With the initial iteration of the assay this might have been the case but is no longer a credible explanation. The present iteration of the assay has been shown not to cross-react with noncardiac isoforms of cTnT [10-14], nor does it detect the isoforms of cardiac cTnT that can be re-expressed in response to skeletal muscle injury. The epitopes for detection of cTnI may be lost in the milieu of renal failure. A substantial percentage of patients on dialysis, therefore, have elevations of troponin, especially cTnT, posing a difficult problem in the ED because the initial samples in these patients may indicate an elevation. Having a baseline cTnT is helpful. The FDA has approved the use of cTnT for risk stratification in patients who are on dialysis, and it is recommended that baseline values be available for comparison. If baseline values are not available, looking for a change in serial values is helpful. Patients who experience rising elevations are far more likely to have acute events than those whose values stay the same. This information does not imply that the latter are false positives only that they are less apt to be associated with an acute event. In a group, such as dialysis patients, where elevations in the absence of acute is-chemic heart disease are common, this is a helpful approach to determine which patients require admission or urgent care and which do not. This same principle seems to be the case in patients who seem to be at risk for re-infarction [71]. Initial guidelines suggested the use of other markers to help in this area, but it is clear clinically, although extensive collaborating data have yet to be developed in the literature, that using rising values are an effective strategy. Thus, dialysis patients who present with rising values are those in need of aggressive care. Patients who present with more chronic elevations can be evaluated more electively assuming no other clinical signs exist pointing to acute disease. This evaluation can include considerations of all other entities capable of causing elevations in troponin, such as pulmonary embolism, congestive heart failure, and the like.

These caveats apply only to patients who are on dialysis. Although there are an increased number of elevations of troponin in patients who present with significant renal dysfunction, most seem to be caused by concomitant co-morbidities and are not synonymous with the chronic elevations seen in dialysis patients. Accordingly, the caveats above should be applied to dialysis patients only. The concept that elevations in troponin with milder forms of renal dysfunction can be attributed to this chronic process is at present unsupported by data. The potential etiologies of troponin elevations in dialysis patients likely are related to the metabolic milieu of dialysis, concomitant endothelial dysfunction, severe hypertension with LVH, acute ventricular stretch, and various other mechanisms that occur in patients who present with renal dysfunction. Delayed clearance of the troponin by way of the kidneys is an unlikely cause of the troponin elevations.

Other etiologies for elevated troponins

As indicated in earlier discussion and in Box 1, acute ischemic heart disease is only one reason for elevations. Many other reasons exist that need to be considered [26]:

1. Many of the entities listed involve some degree of ischemia but it is not ischemia necessarily caused by acute coronary abnormalities. For example, patients who present with left ventricular hypertrophy, whether caused by hypertension, aortic stenosis, or hypertrophic cardiomyopathy, and so forth, are known to have an underper-fused subendocardium. Thus, patients may be at risk if rapid heart rates, hypotension, or hypertension for elevated troponins as a result of injury to the sub-endocardium. When patients have arrhythmias, a similar mechanism could be involved. This mechanism is probably the mechanism for elevations by

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