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Articles |
1
NACB Committee Chair, Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT 06102.
2
Department of Laboratory Medicine and Pathology,
Hennepin County Medical Center and the University of Minnesota,
Minneapolis, MN 55415.
3
Department of Emergency Medicine, University of
Cincinnati, Cincinnati, OH 45267.
4
Division of Cardiology, McGuire Veterans Administration
Medical Center and the Virginia Commonwealth University/Medical College
of Virginia, Richmond, VA 23225.
5
Department of Pathology, Northwest Community Hospital,
Arlington Heights, IL 60005.
6
Department of Pathology and Laboratory Medicine,
University of Louisville School of Medicine, Louisville, KY 40292.
7
Listed with each recommendation is the degree of evidence from the literature and/or agreement from the consensus of participants who attended either presentation. Using a modified classification scheme defined by the American College of Cardiology/American Heart Association (AHA/ACC), the NACB Committee defined a Class I recommendation as one for which there is evidence and/or general agreement; a Class II recommendation as one for which there is conflicting evidence and/or a divergence of opinion about its usefulness/efficacy, but where the weight of evidence/opinion is in its favor; and a Class III recommendation as one for which there is evidence and/or general agreement that a procedure is not useful or effective (4).
a Address correspondence to this author at: Hartford Hospital, Department of Pathology, 80 Seymour St., Hartford, CT 06102. Fax 860-545-3733; e-mail awu{at}harthosp.org
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Abstract |
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 Top Abstract Session I. Recommendations for...Session II. Recommendations for...Session III. Recommendations for...Session IV. Recommendations for...General DiscussionReferences |
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Approximately 100 individuals responded to various versions of these recommendations via direct correspondences, telephone calls to Committee members, electronic mail correspondence to the Committee Chairman, or oral questions and comments raised during one of the two conference presentations. Some of the recommendations were changed to reflect the consensus opinion. In cases in which there was no consensus, the Committee included pertinent discussion without necessarily changing the original recommendations. At times, the Committee members felt that although a particular recommendation might not be the current standard of care today, they anticipate that it likely will be adopted in the near future.
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Session I. Recommendations for Markers in the Triage of Patients with Chest Pain |
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TopAbstractSession I. Recommendations for...Session II. Recommendations for...Session III. Recommendations for...Session IV. Recommendations for...General DiscussionReferences |
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Recommendation: Members of emergency departments, divisions of cardiology, hospital administrations, and clinical laboratories should work collectively to develop an accelerated protocol for the use of biochemical markers in the evaluation of patients with possible acute coronary syndromes.
Strength/consensus of recommendation: Class I.8
For simplicity, this protocol should apply to either the facilitated diagnosis or the rule-out of AMI in the ED or to routine diagnosis from other areas of the hospital, should a patient develop symptoms consistent with acute coronary syndromes while hospitalized.
Strength/consensus of recommendation: Class II.
Many hospitals today have a dedicated area within the ED for the rapid rule-out of AMI. These areas have been designated as "chest pain centers", "heart emergency rooms", or some other terms to indicate that the efficient triage of chest pain patients is a major objective of that center. Essential for early AMI rule-out is frequent electrocardiographic testing and blood collections for the measurement of cardiac markers. Patients with negative results for these tests most likely do not have an AMI. They may, however, have unstable angina or other forms of acute cardiovascular disease. For these patients, it is appropriate to perform additional studies such as a stress test, echocardiogram, or radionuclide ventriculogram for risk stratification. Establishment of a clinical practice guideline for the evaluation of patients with chest pain will reduce the variability of practices among physicians and institutions, at the same time improving the accuracy of triaging decisions (5). The NACB Committee felt that for "routine AMI diagnosis" of patients who are already hospitalized for other reasons, the same criteria should apply as are used in the ED.
Discussion.
Although the recommendation that laboratorians
should work with ED physicians, cardiologists, and hospital
administration may appear obvious, in actual practice, decisions on
testing protocols are often made without input from the laboratory.
Laboratory directors must be aggressive in requesting that qualified
personnel be part of organizational and operating committees when such
discussions are being conducted, or should initiate the discussions
themselves. Understanding the expanded role that the laboratory will
play in creating these rule-out centers will enable justification to
hospital administrators for the additional laboratory expenses that
will be required. This argument will be particularly effective if the
overall objective of reducing in-hospital lengths of stay and the
numbers of unnecessary admissions or wrongful discharges from the ED
can be demonstrated.
The diagnosis of AMI is not always made in the ED. Sometimes patients admitted for other reasons develop symptoms for AMI while in the hospital. Some physicians or administrators may believe that rapid AMI rule-out of hospitalized patients may not be as important as triage for ED patients. Nevertheless, the NACB Committee felt that the same protocol used in the ED is appropriate for routine AMI diagnosis because new therapies for acute coronary syndromes are available, and, when appropriate, should be delivered rapidly. The use of a rapid AMI rule-out protocol will simplify the steps needed from the laboratory’s perspective and provide clinicians optimum diagnostic measures for all patients.
recommendation 2
Although the time of onset of chest pain for AMI patients is often
known, this information often is less available or reliable for
those with unstable angina and other cardiac diseases. It is not
uncommon for these patients to report multiple episodes of chest pain
over the hours and days before ED presentation. Intermittent closure
and spontaneous reperfusion of coronary arteries with ruptured
atherosclerotic plaques reflect the dynamic nature of acute coronary
syndromes. In the elderly or in patients with insulin-dependent
diabetes mellitus type I, there may be altered thresholds or a blunted
response to pain. Indeed, there are many patients with acute coronary
syndromes who experience silent ischemia and infarction (i.e., no pain
during occlusive episodes) (6).
Recommendation: For routine clinical practice, blood collections should be referenced relative to the time of presentation to the ED and (when available) the reported time of chest pain onset.
Strength/consensus of recommendation: Class I.
Discussion.
In the early drafts of the Guidelines, the
recommendations were that all blood collections should be referenced to
the time of ED presentation only. However, many reviewers felt it
important to also note the time of onset of chest pain, especially when
there is a history of a single chest pain event (and not several events
over many days) and when the time of onset as reported by the patient
or family is deemed to be reliable. It may also provide an explanation
as to why some clinical studies fail to document a consistent rise in
the concentration of the marker, e.g., at 6 h, whereas other
studies indicate that the markers were increased at this time point in
all patients (e.g., when the majority of enrolled patients in
the study present beyond 6 h of chest pain).
recommendation 3
The ideal biochemical marker is one that has high clinical
sensitivity and specificity, appears early after AMI to facilitate
early diagnosis, remains abnormal for several days after AMI, and can
be assayed with a rapid turnaround time (7)(8).
Because there currently is no single marker that meets all of these
criteria, a multianalyte approach has the most merit.
Because the interval between the onset of pain and ED presentation
is variable from patient to patient, two markers are needed to enable
detection of patients who present either early or late. Currently,
myoglobin is the marker that most effectively fits the role as an early
marker. A rise in myoglobin is detectable in blood as early as 1–2 h
after onset and can be highly effective for AMI rule-out (Fig. 1
, peak A) (9). Moreover, automated
immunoassays for myoglobin are commercially available. Myoglobin is not
cardiac specific, and patients with renal failure, skeletal muscle
injury, trauma, or disease can have abnormal concentrations in the
absence of AMI (10). The creatine kinase MB (CK-MB) isoforms
(also termed "subforms") have also been shown to be an early marker
for AMI (11). Automated stat CK-MB isoform measurements are
being used in some hospitals as an early measure of myocardial injury.
Moreover, it may also be possible that troponin can be used as an early
marker if a new assays are developed that are more sensitive than
current ones (12). In an ED study, qualitative measurement
of cardiac troponin T and I (cTnT and cTnI) using point-of-care (POC)
devices were reliable for ruling out AMI at 6 h after onset of
symptoms (13). These studies, however, were not confirmed by
a more recent study of chest pain patients that used quantitative
laboratory-based assays for troponin (14). Clearly, more
studies are needed to fully address the role of troponin in early
diagnosis and the comparison between troponin T and I.
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In contrast, cTnT and cTnI are currently the best markers for
definitive AMI diagnosis. Troponins appear in the serum relatively
early after the onset of symptoms (4–12 h) and remain abnormal for
4–10 days (Fig. 1
, peak B). Results are not increased in the presence
of skeletal muscle troponin (15)(16). Early
studies have questioned the clinical specificity of cTnT assays in
patients with chronic renal failure (17)(18).
With the development of a second-generation ELISA assay for cTnT, the
frequency of positive results in these patients is lower than the
frequency in the first-generation assay, although still higher than for
cTnI (19)(20). Western blot analysis on
regenerating human skeletal muscle tissue showed that the cardiac
isoforms of troponin T are expressed in pathologic conditions (such as
polymyositis and muscular dystrophy) (21). However,
subsequent studies have shown that the antibodies used in the Roche
commercial assays are specific for myocardial cTnT isoforms, do not
detect the cTnT isoforms expressed in diseased skeletal muscle, and
therefore, do not produce false-positive cTnT results in renal patients
(22)(23). Preliminary outcomes studies have
shown that chronic renal failure patients who have high cTnT
concentrations in blood have a higher incidence of cardiac death than
those with normal concentrations, confirming the notion that troponin
is measuring true myocardial injury that is not associated with or
classified as an AMI (24). The importance of these
findings is not completely known. Are there therapies that can be
administered to reduce the short-term mortality of renal failure
patients with a positive troponin result? How does risk stratification
with troponin compare with other indicators of renal function? One
study showed that measurement of the troponins in patients with both
acute coronary syndromes and renal insufficiencies reduces the
effectiveness for risk stratification of chest pain patients based on
cTnT and cTnI monitoring (25). These and other questions
will need to be the focus of future studies.
Recommendation: Two biochemical markers should be used for routine AMI diagnosis: an early marker (reliably increased in blood within 6 h after onset of symptoms) and a definitive marker (increased in blood after 6–9 h, but has high sensitivity and specificity for myocardial injury, remaining abnormal for several days after onset).
Strength/consensus of recommendation: Class II.
Discussion.
The merits of myoglobin as the early
marker have been debated by many reviewers and conference participants.
Although there is ample literature suggesting that myoglobin is an
early marker (26)(27)(28), there are reports that support the
view that myoglobin is not any earlier than CK-MB mass assays
(29). These reviewers feel that the poor specificity of
myoglobin (in the presence of skeletal muscle disease or renal failure)
does not justify its routine use as a cardiac marker. However, there is
increasing pressure by ED physicians and hospital administrators to
rule out AMI sooner. Some chest pain centers have begun to discharge
patients within 6 h of ED presentation. CK-MB is not reliably
increased at this interval after AMI, and myoglobin may have a role in
this situation. As an alternative to myoglobin, a minority of
laboratories have begun using CK-MB isoforms as an early AMI marker
(30). (In a poll taken during the AACC Annual Meeting, <1%
of conference participants indicated that they were currently using
isoforms.) Currently, CK-MB isoforms are most effectively measured by
high-voltage electrophoresis (31). With improvements in
analytical methodologies, the number of laboratories routinely using
isoforms might increase. The NACB Committee recognizes the limitations
of myoglobin and CK-MB isoforms and encourages continued research into
earlier markers, particularly if they are more specific for myocardial
necrosis. In the meantime, the NACB Committee believes that myoglobin
is an earlier marker than CK-MB mass and is more conveniently measured
on automated immunoassay analyzers than CK-MB isoforms.
recommendation 4
Large studies in New York and Texas have shown that ~50% of AMI
patients will present to the ED with evidence of acute myocardial
injury on the electrocardiogram (ECG) (32). Acute
intervention with thrombolytic therapy or angioplasty should be
considered in those patients who present within 12 h after the
onset of symptoms (33)(34). Specific ECG changes
are highly diagnostic for AMI when interpreted by well-trained
physicians (35).
Recommendation: In patients with a diagnostic ECG on presentation (ST-segment elevations, presence of Q waves or left bundle branch block in two or more contiguous leads), the diagnosis of AMI can be made and acute treatment initiated without results of acute cardiac marker testing.
Strength/consensus of recommendation: Class I.
In AMI patients with diagnostic ECGs, biochemical marker testing at a reduced frequency of blood collection (e.g., twice per day) is valuable for confirmation of diagnosis, to qualitatively estimate the size of the infarction, and to detect the presence of complications such as a reinfarction.
Strength/consensus of recommendation: Class I.
Discussion.
The NACB Committee sought advice from ED
physicians and cardiologists as to why cardiac markers are still being
ordered on patients with ECG-documented AMI, when in many cases,
therapy had already been initiated before results of tests were
available from the laboratory. Although most physicians recognize that
in this context, these tests do not serve a diagnostic role, many felt
that biochemical documentation of AMI was necessary to complete the
triad of criteria established by WHO for AMI diagnosis
(36). It is also likely that a positive result for a cardiac
marker in these patients provided a level of comfort and confidence to
the attending staff. Many physicians also felt that knowing the peak
concentration of a cardiac marker provided a qualitative estimate of
infarct size (without calculating the area under the curve of marker
concentration vs time). This information might have a role in the
future management of surviving AMI patients.
Many conference participants also felt that continued measurement of
markers was helpful in detecting the presence of a reinfarction,
estimated to be 17% of AMI patients (37). If the
reinfarction occurs before there is complete clearance of the marker
from the original infarct, it might not be possible to detect the
presence of the reinfarction because the markers released from the
second event might be indistinguishable from that released by the
initial event. For this reason, the use of cardiac markers that return
to baseline concentrations early may have an advantage over the use of
markers that are slow to clear from the circulation. For example,
myoglobin and CK-MB isoforms return to reference values
typically within 24 h after AMI (Fig. 1
, peak A). If a
reinfarction were to occur after this time, increases in the
concentration or activity of these proteins would enable detection of a
second necrotic event. CK-MB mass can also be considered as a
reinfarction marker that returns to baseline concentration reasonably
early (but not as early as myoglobin). Many reinfarctions occur between
7 and 14 days after the initial event. Because CK-MB remains abnormal
for 3–4 days (Fig. 1
, peak C), CK-MB may be useful to detect a
reinfarction even if the event is not immediately suspected by the
medical staff. CK-MB mass would show a secondary increase, whereas
myoglobin and CK-MB isoforms could have returned to baseline
concentrations (Fig. 1
, peak A). Alternatively, one could request that
the laboratory retrieve a stored specimen for myoglobin or isoform
testing if available because serum myoglobin is stable for several days
if refrigerated (38), and isoforms are stable when collected
with EDTA (39).
recommendation 5
For AMI rule-out of patients who have equivocal ECG changes,
cardiac markers play an essential diagnostic role in non-Q-wave AMIs.
Unfortunately, there is great variability between hospitals in the
frequency of blood collections. In 1986, the American College of
Physicians recommended a conservative testing guideline based on
total CK and CK-MB for blood collected on admission and at 12 and
24 h after admission, and the use of lactate dehydrogenase
isoenzymes when admission is >24 h after onset (40). The
NACB Committee believes that this strategy is no longer adequate to
meet the current triaging
needs.
Rule-out of AMI requires serial collection and testing of blood for cardiac markers. When an early marker such as myoglobin is used, acute myocardial necrosis can be effectively ruled out within 6–9 h after ED presentation (41)(42), and a decision to discharge the patient to home or a to low care level bed can be considered. On the other hand, for AMI rule-in, a single positive result for either troponin T or I would trigger a diagnosis of AMI and triage of the patient to the appropriate level of care (13), without the need for necessarily completing this algorithm (43)(44). This recommendation was made because, unlike myoglobin, CK, CK-MB, and lactate dehydrogenase, positive results for cTnT and cTnI are highly indicative of myocardial damage, with no release of these proteins from skeletal muscles or other tissues (45)(46).
Recommendation: For detection of AMI by enzyme or protein markers, in the absence of definitive ECGs, the following sampling frequency is recommended:
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Strength/consensus of recommendation: Class II.
Discussion.
The need to perform the 2–4 h blood
collection for the late marker can be questioned. In particular,
negative results at admission and at 2–4 h after admission for
myoglobin, and a negative result for cardiac troponin at admission
would obviate the need for measuring troponin in the 2–4 h sample. The
NACB Committee felt that most laboratories do not currently have a
mechanism for automatic "reflex testing" (i.e., testing that
involves the ordering or cancellation of follow-up tests on a given
sample based on results of preliminary tests). Therefore, it is
more convenient for the laboratory to perform testing for both markers
on all samples, rather than to hold specimens until results of
preliminary tests (i.e., the early markers) are known.
Among chest pain centers, there are many variations to the protocol for blood sampling and the total number of samples needed for AMI rule-out. Some centers use intervals of every 3 h, whereas others use every 4 h. In one study, chest pain patients were triaged on the basis of only two samples collected: one at admission and one at 4 h (13), with a third sample collected only on patients presenting with <2 h history of chest pain. Because of the unreliability of the chest pain history, the NACB Committee has taken a more conservative approach of recommending the collection of at least three blood samples during the early triage period. A blood collection at 12–24 h may be useful for the detection of reinfarction or myocardial extension or for risk stratification of patients with unstable angina. Investigators have found that a 16-h blood sample adds additional value for risk stratification over the initial blood sample (47).
recommendation 6
Some EDs are slow to develop a rapid rule-out chest pain center
because of financial limitations, space, and/or a lack of knowledge of
the potential benefits. In these centers, the extra laboratory tests
bring additional costs without benefits in terms of reduced hospital
lengths of stay or frequency of inappropriate discharges of patients
with AMI.
Recommendation: For those EDs in which patient triage decisions are not made within the first few hours after ED presentation, the use of an early marker such as myoglobin may be unnecessary. In this case, only one definitive marker such as cardiac troponin is needed. The frequency of blood collection should also be reduced.
Strength/consensus of recommendation: Class I.
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Session II. Recommendations for Markers in Acute Coronary Syndromes |
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TopAbstractSession I. Recommendations for...Session II. Recommendations for...Session III. Recommendations for...Session IV. Recommendations for...General DiscussionReferences |
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Original validation studies for cardiac troponin assays have compared
results against CK-MB for the diagnosis of AMI. When the upper limit of
normal is used as the cutoff concentration, clinical studies have shown
that cardiac troponin was less specific for AMI diagnosis than CK-MB
mass (50) when the classical WHO definition of AMI was used
(36). This was because assays for cardiac troponin were
detecting myocardial injury in some cardiac patients (e.g., those with
unstable angina) with CK-MB below the cutoff (Fig. 1
, peak C),
and the extent of damage was insufficient to produce ECG patterns that
were indicative of AMI. A higher cutoff concentration could be used to
mimic the clinical specificity of CK-MB for AMI. However, this will
lead to the loss of clinically useful information because the
importance of detecting myocardial injury (Fig. 1
, peak D) has been
demonstrated in retrospective outcomes studies in patients with
abnormal concentrations of cTnT (51)(52)(53) or cTnI
(54)(55)(56). These studies define a population that is at high
short-term risk (<6 weeks) for adverse events (AMI and cardiac death).
Cumulative metaanalyses suggest that the odds ratio for adverse
events of a high troponin in unstable angina are 5:1 relative to a
cohort of chest pain patients with normal troponin results
(57). The risk is additive: the higher the cTnT and cTnI
concentrations in blood, the higher the prospective risk
(56)(58). Thus, the detection of a low degree of
myocardial injury is possible with the use of a low cutoff
concentration for cardiac troponin (e.g., the upper limit of the
reference interval), a strategy that is less applicable for nonspecific
markers such as CK-MB.
The methodology for assignment of the low and high cutoff concentrations for cardiac troponin or any other cardiac marker is discussed in Session III under "Recommendation 5".
Recommendation: Two decision limits are needed for the optimum use of sensitive and specific cardiac markers such as cTnT or cTnI. A low abnormal value establishes the first presence of true myocardial injury, and a higher value is suggestive of injury to the extent that it qualifies as AMI, as defined previously by WHO (36).
Strength/consensus of recommendation: Class II.
Discussion.
The concept of two decision limits for
cardiac troponin was highly debated during the presentation of the
Guidelines. A survey indicated that slightly more participants would
prefer the use of a single cutoff concentration set at the lower of the
two decision limits, rather than define two separate limits. No one
suggested the use of a single cardiac troponin decision limit set at
the AMI cutoff concentration. Many felt that the use of two
limits overly complicates the situation and would require a substantial
amount of physician education. Others felt that the therapeutic
approaches for patients with unstable angina and non-Q-wave AMI are
identical and that a differentiation between these two groups is,
therefore, unnecessary.
The NACB Committee agreed with the consensus that detection of any myocardial injury was important (51), thereby justifying the use of a single low cutoff concentration for cardiac troponin. However, the Committee felt that use of a more sensitive cardiac marker (in a patient with a positive history of chest pain) would double the number cases of AMI compared with using the existing WHO criteria, which are based on the use of enzyme markers. It is important to not classify these patients as AMI, because they may be disadvantaged from a social, psychological, and socioeconomic standpoint (59). It may also affect how the hospital gets reimbursed for these services. Until the criteria for diagnosis of AMI are redefined by WHO or other clinical groups such as the American Heart Association or the American College of Cardiology, the NACB Committee recommends a two-cutoff designation for cardiac troponin; a low limit that detects a small amount of myocardial injury but classifies those patients at high risk, and a higher limit with the amount of injury present is to the extent that it conforms with a WHO-defined AMI.
recommendation 2
In the past, CK-MB results between the upper limit of normal
and the AMI decision limits had been termed a "gray zone". This
practice was appropriate because CK-MB was not specific for the heart,
and there were healthy subjects who had measurable CK-MB
concentrations from skeletal muscle release within this range. The use
of a low CK-MB cutoff would cause many of these patients to be
incorrectly classified as having high cardiac risk. For cTnT and cTnI,
the term gray zone should not be used because it connotes uncertainty
in clinical interpretation.
Recommendation: Chest pain patients with laboratory results for cTnT and cTnI between the upper limit of the reference interval and the decision limit for AMI should be labeled as having "myocardial injury". These patients should be admitted and acutely treated to reduce the risks associated with this injury (60)(61).
Strength/consensus of recommendation: Class I.
Discussion.
In the original draft of these Recommendations and
in some early literature reports on cardiac troponin [e.g., Ref.
(62)], abnormal troponin results occurring in some non-AMI
patients with CK-MB within the reference interval were
designated as having "minor myocardial injury or damage". The
descriptive term, "minor" meant that the amount of tissue damage
occurring to the heart was significantly less than that which occurs in
patients with AMI. However, many conference participants felt that use
of this term might be interpreted by physicians as minor risk for
future untoward cardiac events, which is not true. In fact, unstable
angina patients with abnormal concentrations of troponin may be at
greater risk than surviving AMI patients because therapeutic options
such as intravenous thrombolytic therapy are not available for the
non-AMI patient. Other terms have been suggested that might better
describe the clinical importance of this finding, such as
"microinfarct" or "infarctlet", or suggest that these patients
have suffered a non-Q-wave AMI (63). Perhaps in some
future clinical guideline, the term "acute myocardial infarction"
can be eliminated entirely and replaced with "acute coronary
syndromes". In this way, a single cutoff concentration for a cardiac
marker such as troponin can be justified. This would reflect the
incremental risks associated with increasing concentrations of the
marker, consistent with the continuous injury concept of acute coronary
syndromes.
In the current version of these Guidelines, the term minor has been removed. Excluding situations where the cardiac troponin was increased because of a problem with the assay’s analytical specificity, all patients with an abnormal concentration of troponin have myocardial injury and should be viewed as having cardiovascular risk. It is the responsibility of the ordering physician to use this information in the context of other data in making the appropriate management decision.
It is also important to recognize that because troponin is increased for many days after AMI, it may be possible that without a full clinical history, small increases in troponin with a negative CK-MB might simply reflect an AMI in which CK-MB had returned to normal. Because of this fact, some might advocate keeping CK-MB mass assays available for this purpose. However, myoglobin could also fulfill this need because it would be normal in these late-presenting AMI patients. Myoglobin would might be available if the recommendations for two cardiac markers for ED triaging were followed by an institution.
recommendation 3
WHO has defined the diagnosis of AMI as a triad (36).
Two of which must be present for diagnosis:
With the development of biochemical markers that are not themselves enzymes, such as cTnT, cTnI, and myoglobin, the third criterion of the WHO triad should be revised.
Recommendation: The WHO definition of AMI should be expanded to include the use of serial biochemical markers and not be limited to enzyme changes. It should be emphasized that rule-out of AMI cannot be made on the basis of data from a single blood collection. However, when very specific cardiac markers are used, the presence of an abnormal concentration from a single specimen can be highly diagnostic of myocardial injury.
Strength/consensus of recommendation: Class I.
Discussion.
The NACB Committee recognizes that clinical groups
will have to lobby WHO to make substantive changes to their criteria
for AMI diagnosis. This will require an international effort by
cardiologists, emergency physicians, and laboratorians. Thus, the above
recommendation is included to justify the use of myoglobin and cardiac
troponin, and perhaps future non-enzyme protein markers that will have
been shown to have value in the diagnosis of AMI.
recommendation 4
The analysis of blood for lipids such as cholesterol and
lipoproteins such as LDL and HDL is well established in the assessment
of coronary artery disease risk (64). As such, these markers
are being used to screen asymptomatic individuals. Because sensitive
cardiac markers have also been shown to provide information on risk
stratification, there may be an impetus to use these markers as part of
a biochemical panel for routine health screening to detect the presence
of silent ischemia, or after exercise stress testing to detect presence
of ischemic injury.
Studies of biochemical markers before and after nuclear ventriculography of chest pain patients have shown that neither cTnT or cTnI is increased after stress testing, even in patients with documented evidence of flow defects (65).
Recommendation: At this time, there are no data available to recommend use of cardiac markers such as cTnT or cTnI for screening asymptomatic patients for the presence of acute coronary syndromes. The likelihood of detecting silent ischemia is extremely low and cannot justify the costs of screening programs. Additionally, there is no evidence that cardiac marker analysis of blood following stress testing can indicate the presence of coronary artery disease.
Strength/consensus of recommendation: Class III (for use of cardiac markers for screening).
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Session III. Recommendations for Markers in Clinical Applications Other than AMI and Research |
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TopAbstractSession I. Recommendations for...Session II. Recommendations for...Session III. Recommendations for...Session IV. Recommendations for...General DiscussionReferences |
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When reperfusion is successful, it is produced in the majority of cases within 90 min after the initiation of therapy (68)(69)(70). Sampling blood at 60 after the initiation of therapy may be helpful in the early determination of successful reperfusion, but cases of late recanalization could be missed. Some investigators have suggested a 120-min sample (71). Although this time interval is also acceptable, it could delay any subsequent management decision. Other investigators have used the time to peak marker concentration as the discriminating factor. This is not recommended because it requires more blood sampling and could produce further delays in interpreting results. This is particularly true for patients who have permanent occlusions.
Recommendation: For assessment of reperfusion status following thrombolytic therapy, at least two blood samples are collected and marker concentrations compared: time = 0, defined as just before initiation of therapy, and time = 1, defined as 90 min after the start. From these values, the determination of the (a) slope value [(markert = 90 - markert = 0)/90 min]; (b) absolute value of markert = 90, in minutes; or (c) the ratio of markert = 90/markert = 0 can be used as the discriminating factor between successful and unsuccessful reperfusion. However, monitoring with biochemical marker strategies has not been successful in distinguishing between TIMI grade 3 and TIMI grade 2 flow patients, rendering the utility of these measurements clinically problematic for determining complete reperfusion.
Strength/consensus of recommendation: Class II.
recommendation 2
Cardiac markers have also been used to detect the presence of
perioperative AMI in patients undergoing surgical procedures
(72). The use of nonspecific cardiac markers such as CK,
CK-MB, myoglobin, and lactate dehydrogenase have limited usefulness
because they are released from noncardiac tissues as a consequence
of the procedure itself (73).
The performance of cardiac troponin for the detection of perioperative AMI has been shown to be superior to other cardiac markers such as CK-MB (74)(75). However, a protocol for the frequency of blood collection and interpretation of results will require more clinical studies before specific recommendations can be made as to the appropriate decision limit for perioperative AMI. These studies should answer several questions. Can the existing AMI decision limits be used? If the surgical procedure involves the heart, e.g., coronary artery bypass graft, some injury to the myocardium itself is expected. Should a higher AMI decision limit be used in open heart surgeries? It has been shown, for example, that a cTnT concentration of 0.6 µg/L (sixfold higher than the recommended 97.5% upper reference limit cutoff) had a positive predictive value for an adverse outcome of 87.5%, with a negative value of 98% (76). More studies in which cutoff concentrations are optimized to outcomes are needed.
Recommendation: cTnT or cTnI should be used for the detection of perioperative AMI in patients undergoing noncardiac surgical procedures. The same AMI decision limit should be used.
Strength/consensus of recommendation: Class I.
recommendation 3
Cardiac markers have been used in other monitoring
roles, such as myocardial infarct sizing. Infarct sizing involves
serial collection of cardiac markers and integrating the area under the
curve of a plot of enzyme activity or protein concentration vs time.
Such calculations produce an estimate of the quantity of
infarcted tissue that correlates to anatomic estimates of infarct size
made at autopsy (77). For cardiac markers that exhibit the
washout phenomenon, infarct-sizing estimates are inaccurate when
reperfusion of occluded coronary arteries is successful
(78). Other markers that are not sensitive to reperfusion
status, such as myosin heavy chains (79), may provide more
accurate infarct-sizing estimates. However, commercial assays are not
readily available for myosin light chains.
Assessment of infarct sizing, however, may be useful as a research tool in clinical trials of new drugs (e.g., intravenous thrombolytic therapy, thrombin inhibitors, and glycoprotein IIb/IIIa inhibitors) or procedures (e.g., angioplasty) designed to limit the extent of myocardial injury, or in studies involving the injury that occurs when an occluded artery is suddenly reperfused (80).
Recommendation: Cardiac markers should not be routinely used for infarct sizing because the existing markers are inaccurate in the presence of spontaneous, pharmacologic, or surgical reperfusion.
Strength/consensus of recommendation: Class III (for use of markers in infarct sizing).
recommendation 4
New markers will continue to be developed and
examined for patients with acute coronary syndromes. When a marker such
as cardiac troponin demonstrates major advantages over existing
markers, there is an urgency of manufacturers to develop and market
commercial assays. In the specific cases of CK-MB mass and cTnI assays,
there were no cooperative attempts to develop reference materials or to
standardize results.
The NACB Committee acknowledges that the exclusive release of new markers may be in the manufacturer’s best interests in terms of profitability, and therefore, they may be reluctant to share ideas and needs with their colleagues. Nevertheless, the implementation of new tests is more easily integrated into the laboratory when these markers are available on a wide spectrum of analyzers, and it is in the best interests of the medical community and the in vitro diagnostic industry that assays correlate to one another.
Recommendation: Early in the process, manufacturers should seek assistance and provide support to professional organizations such as the AACC or IFCC to develop committees for the standardization of new analytes. These organizations will determine the need for analyte standardization based on the potential clinical importance of the marker and gather the necessary scientific expertise for the formation of a standardization committee.
Strength/consensus of recommendation: Class I.
Discussion.
The IFCC has established the Committee
on Standardization of Markers of Cardiac Damage to coordinate the
ongoing worldwide activities in this area. This Committee will be
working with national clinical chemistry societies, such as the AACC
and the German Society for Clinical Chemistry, in their efforts to
standardize cTnI and myoglobin, respectively. cTnT is only available
from one manufacturer, and standardization is not now an important
issue.
recommendation 5
Utilization of a new test requires the establishment of a
reference interval. This is achieved by measuring the concentration of
the marker in a cohort of apparently healthy subjects. For cardiac
markers, a separate "decision limit" is used to differentiate
between AMI and non-AMI diagnoses. The decision limit is typically
higher than the upper reference limit. Establishment of these limits is
essential for the proper interpretation of results.
For cardiac markers, only the upper limit of the reference interval is needed because there is no significance for results that are below the lower reference limit. The first lower decision limit is defined as the upper 2.5 percentile (one-tail test) of results from a healthy population (81). This statistical approach is commonly used to assign reference interval concentrations (82). For nonspecific markers such as CK, CK-MB, or myoglobin, the reference interval is for reference only and is not used for clinical decisions. For specific marker such as cardiac troponin, the upper reference limit is used to establish the presence of cardiac injury (see Session II, "Recommendations 1 and 2").
The AMI cutoff concentration is determined by ROC analysis of results from marker concentrations collected within the established diagnostic window on a population of consecutive chest pain patients presenting to the ED for AMI rule-out. The patients must be diagnosed as having an AMI independent of the experimental cardiac marker being tested, by accepted and rigorously applied criteria (e.g., WHO). However, as part of the AMI diagnosis criteria, one cannot avoid use of accepted cardiac markers (such as CK-MB) that are in routine use at the facility. Recommendations for the standardization of ROC curves have been published (83). These published guidelines suggest that decision thresholds be printed on the ROC curve, the determination of the area under the ROC curve (including standard error and the confidence interval) and calculation of P (or z) when two or more markers are compared on the same ROC plot. Decision limits provided by reagent manufacturers that are not rigorously determined according to the above recommendation should be considered as guidelines and should not substitute for ROC analysis.
Recommendation: Reference intervals are established for each marker on a population of healthy individuals, using the 97.5 percentile (one-tail) of results. Separate cutoff concentrations for results indicative of AMI are also necessary for all cardiac markers. Standardized ROC curves should be used to establish AMI decision limits, using carefully selected and diagnosed patient populations.
Strength/consensus of recommendation: Class I.
Discussion.
There was substantial discussion as to
how the first troponin cutoff concentration for the detection of
myocardial injury should be established. Ideally, this cutoff should be
determined empirically with a retrospective analysis of patients with
acute coronary syndromes in which the clinical outcomes of these
patients are assessed after 4–6 weeks. Using logistic analysis, the
value that produces the highest odds ratio for predicting short-term
outcomes would be selected as the cutoff concentration. Because
such a study is impractical for most hospital laboratories, the
upper 2.5 percentile recommendation was made. Other reviewers felt that
any detectable troponin indicates cardiac injury, and therefore, the
detection limit should be used as the lower cutoff. This might have
been acceptable for insensitive assays in which all healthy subjects
are below the detection limit. However, improved cardiac troponin
assays are being developed that are more sensitive than previous
versions, and these assays enable detection of baseline concentrations
of cardiac troponin in healthy subjects. Residual troponin
concentrations in these subjects represent normal apoptotic turnover of
myocardial tissue and not true ischemic myocardial damage
(84). Setting the cutoff at the upper 2.5% of the reference
population will be directly applicable when more sensitive become
available.
recommendation 6
Much of the focus for new markers has been on the discovery and
evaluation of markers that can detect the initial pathophysiologic
events of acute coronary syndromes, such as inflammation, thrombus
formation, platelet aggregation, and reversible ischemia. Some of the
markers examined for these processes include C-reactive protein
(85) amyloid protein A (86), thrombus precursor
protein (87), p-selectin (88), and glycogen
phosphorylase isoenzyme BB (89). Other markers that may be
used in place of or to improve the specificity of myoglobin include
heart fatty acid-binding protein (90) and carbonic anhydrase
III isoenzyme (91). For research studies involving
these new markers, the time of admission is not useful when the results
are compared with conventional markers such as myoglobin, CK-MB, and
cardiac troponin because the interval between the onset of clinical
symptoms and ED admission is variable from institution to institution
(92).
Recommendation: For research studies involving the kinetics of release and appearance of new biochemical markers, the time course of release and appearance in blood must be defined relative to the onset of clinical symptoms.
Strength/consensus of recommendation: Class I
The diagnostic accuracy of these new markers may be compromised if the diagnosis of AMI for study patients is based on standard enzyme markers that themselves have sensitivity and/or specificity limitations (e.g., total CK and CK-MB). Therefore, AMI diagnosis should be defined by WHO criteria, but with the substitution of "unequivocal serial changes of cTnT or cTnI" as the principal biochemical marker, in place of the current WHO criteria of "unequivocal serial enzyme changes".
Strength/consensus of recommendation: Class II.
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Session IV. Recommendations for Assay Platforms and Markers of Acute Myocardial Infarction |
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TopAbstractSession I. Recommendations for...Session II. Recommendations for...Session III. Recommendations for...Session IV. Recommendations for...General DiscussionReferences |
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, peak C). The use of CK-MB should be phased out over the ensuing years as more cTnT and cTnI assays become available and the cost for such assays becomes competitive with CK-MB mass assays (94). If a hospital is already using cTnT or cTnI, the NACB Committee felt that the measurement of lactate dehydrogenase isoenzymes and ß-hydroxybutyric dehydrogenase should be discontinued immediately (16)(95) No recommendation is being made as to the discontinuance of assays for total CK. This marker is inexpensive and readily available in clinical laboratories, and it can be very useful for the detection of skeletal muscle injury or disease (96).
Recommendation: Cardiac troponin (T or I) is the new standard for diagnosis of myocardial infarction and detection of myocardial cell damage, replacing CK-MB.
Strength/consensus of recommendation: Class II.
There is no longer a role for lactate dehydrogenase and its isoenzymes in the diagnosis of cardiac diseases.
Strength/consensus of recommendation: Class I.
Discussion.
There was considerable discussion as to whether
cardiac troponins can now replace total CK and/or CK-MB. As summarized
in Table 1
, there are several ongoing analytical issues that have
inhibited a more rapid conversion toward cardiac troponin. For cTnT,
the first-generation assay had a problem with nonspecific binding of
skeletal muscle troponin (corrected with the subsequent generation of
assays). For cTnI, a major issue is the lack of standardization.
Results from different manufacturers produce cTnI values that differ by
a factor of 20 or more (97). Within-run and total
imprecision also are not uniform between commercial assays
(98). In many assays for cardiac troponin, the presence of
fibrin clots and heterophile antibodies can produce false-positive
results (99). False-positive cardiac troponin results have
led to cardiologists performing unnecessary cardiac catheterizations
(personal observations of NACB Committee members). These problems have
prompted manufacturers of troponin assays to produce new generation
kits to improve assay sensitivity and specificity.
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Cardiologists have also expressed concerns about totally replacing CK-MB. Although quantitative calculations using the area under the CK-MB vs time curve are seldom made, many physicians use peak CK-MB to get a qualitative impression as to the size of a myocardial infarction. Others have questioned whether serial troponin measurements can be used for reinfarction (because of the prolonged release pattern) and suggest a continuing role for CK-MB for this purpose. Still others feel that there has not been enough peer-reviewed publications on various troponin assays (particularly cTnI) or day-to-day experience by practicing cardiologists to warrant a change at this time. The NACB Committee felt that over the ensuing years, most of these issues will be resolved. Therefore, despite the existence of these limitations, hospitals should begin considering the replacement of CK-MB at their institutions.
An important issue that must be resolved at each institution is reimbursement for these tests. Recently, the Health Care Finance Administration announced that "it is not necessary to use troponin in addition to creatine kinase (CPT codes 82550-82554) (which includes the MB isoenzyme) in the management of patients with myocardial infarctions", suggesting that reimbursement will not be given when both tests are ordered (100). Private insurance companies may also limit reimbursements for cardiac markers (e.g., Blue Cross/Blue Shield of Michigan does not reimburse for cardiac troponin). Although the Guidelines recommend the use of troponin as the new standard for myocardial injury, the NACB Committee recognizes that it is unrealistic for a hospital or medical center to completely change over to cardiac troponin without a "transition period", during which both CK-MB and cardiac troponin assays are offered. The length of the transition period could be 3–6 months, depending on the acceptance and understanding of the use cardiac troponin results by the medical staff and the degree of continuing education available. After the trial period, the data should be reviewed and a decision made as to whether to (a) continue the trial period, (b) keep CK-MB, (c) replace it with one of the cardiac troponins, or (d) make routine use of both CK-MB and cardiac troponin.
During the presentations, the NACB Committee took a poll as to whether a recommendation can be made now to retire CK-MB. The majority felt that CK-MB still had a role. However, when the conference participants were asked about the future (5 years) use for CK-MB, essentially all felt that CK-MB would eventually be abandoned. The NACB Committee has retained this recommendation because the NACB believes that it should take a leadership role in recommending future clinical laboratory practices. The publication of the recommendation as written may provide documentation and assist laboratory directors and administrators to make changes in testing policies sooner. If laboratories are to retain CK-MB, the NACB Committee recommends the use of mass assays, which have been shown to be superior to activity-based assays (such as immunoinhibition or electrophoresis) (29)(101). The calculation of the percent relative index [CK-MB (in µg/L)/total CK (in U/L) x 100] may assist in the differentiation between myocardial and skeletal muscle causes of increased total CK (102)(103). Other investigators have concluded that the relative index unacceptably degrades the sensitivity of CK-MB and should be abandoned (104)(105).
recommendation 2
AMI patients with ST-segment elevations on the ECG can be
effectively treated with thrombolytic therapy, particularly if therapy
is initiated within 12 h after the onset of chest pain. Delays in
implementation will reduce the success of this treatment. As such, the
National Heart Attack Alert Program has made a recommendation
to physicians to treat all AMI patients within 60 min of their arrival
in the ED (106). Results for serum cardiac markers are not
needed in making this therapeutic decision. However, rapid testing and
reporting of cardiac marker concentrations may produce other
benefits for cardiac patients. Two outcome studies have shown that
testing cardiac markers on a continuous random-access basis decreased
the length of stay and overall laboratory costs compared with testing
on a batched basis (107)(108). It is presumed
that providing stat testing will lead to more time-efficient decisions
for triage and discharge.
The factors that affect TATs include the delay in the delivery of
the sample to the laboratory, the preanalytical steps necessary to
prepare the sample, the analysis time itself, and the effort it takes
to deliver results to the ordering physician. The NACB Committee
understands that the time taken for the delivery of samples to the
laboratory is not always under the control of the laboratory.
Nevertheless, laboratory personnel should work closely with hospital
administrators and nursing staffs to minimize delays. TATs can be
improved with the implementation of pneumatic tubes that deliver
samples directly and rapidly to the central laboratory. The use of
satellite laboratories is another mechanism to reduce delivery and,
therefore, reporting turnaround times. Fig. 2
summarizes the steps necessary for reporting a laboratory
result for cardiac markers.
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Recommendation: The laboratory should perform stat cardiac marker testing on a continuous random-access basis, with a target turnaround time (TAT) of 1 h or less. The TAT is defined as the time from blood collection to the reporting of results.
Strength/consensus of recommendation: Class II.
Discussion.
There was considerable discussion on the
issue of TAT. There was some support for further reducing TATs. When
questioned during the plenary lecture, Dr.Eugene Braunwald
responded that 40 min was a target for ED TAT. One reviewer stated that
new technologies for sample delivery, bar-coding, and rapid
centrifugation will enable laboratories to consistently meet this goal
and that the NACB should begin to set very high standards. Decreasing
TATs would invariably be received positively by the ED staff if they
themselves were not responsible for the testing. On the other hand,
other individuals felt that although the technology for rapid TATs
exists, many hospitals have limitations in human resources. Thus, if a
sample sent from the ED for cardiac markers is accompanied by a request
for a complete blood count, blood gases, electrolyte profile, gram
stains, and other tests, the bench technologist must prioritize which
test to perform first. When a choice is presented to the ED staff as to
which stat analytes should be tested first, a cardiac marker panel
might not have the highest priority. Because of the lack of consensus,
the NACB Committee has retained the recommendation of a 1-h TAT
objective. It is unlikely that a laboratory will be able to
consistently (>90%) deliver stat cardiac marker
results in <30 min, using laboratory-based serum or plasma
assays. Results of stat cardiac marker testing will not be used to
determine the need for thrombolytic therapy. Moreover, rule-out of AMI
from the ED does require results of serial sampling, which further
diminishes the need for a very rapid TAT on any single sample.
recommendation 3
Some laboratories do not have automated immunoassay
analyzers, rapid tube delivery systems, or staffing to deliver results
within 1 h on a continuous basis.
Qualitative as well as quantitative POC testing devices are now available for myoglobin, CK-MB, cTnT, and cTnI (109)(110)(111)(112). These assays make use of anticoagulated whole blood, and have TATs of <20 min. Eliminating the need to deliver samples to the central laboratory and centrifugation enables TATs of <30 min. In a recent randomized study, results obtained with POC testing were compared with results obtained in a central laboratory for consecutive admissions to a coronary care unit (113). The POC testing group was associated with a shorter assay TAT (5 min vs 69 min) and coronary care unit length of stay (1.94 vs 2.51 days) compared with testing performed in the central laboratory. (Because of the small number of subjects, the difference in coronary care unit length of stay did not reach statistical significance.) Recently, multipanel quantitative POC testing devices have been approved by the Food and Drug Administration for combinations of myoglobin, CK-MB, and cTnI. Quantitative assays may ultimately be more useful than qualitative POC devices. However, because ofthe newness of quantitative POC assays, there have been no studies to compare the effectiveness of qualitative vs quantitative POC testing in the ED. Therefore, the NACBCommittee was unable to formulate a recommendation at this time. In some qualitative and quantitative POC testing devices, the total number of analytes measured is fixed. Despite this, the NACB Committee endorses the use of only two: an early (myoglobin or CK-MB mass) and a definitive (cardiac troponin).
Although outcome studies have shown that stat testing and reporting of results for cardiac markers reduces hospital length of stay and laboratory costs for cardiac patients (107)(108), there are no outcome studies to validate the specific need for a 1-h TAT. It is clear, however, that early treatment of Q-wave AMI patients with thrombolytic therapy is important for success in terms of reducing mortality and increasing the rate of coronary artery patency. With the development of new therapeutic strategies for unstable angina and non-Q-wave AMI, the NACB Committee anticipates that early detection of any myocardial injury will also be beneficial in the management of these patients. For those patients who are ruled out for acute coronary syndromes, it is expected that fast TATs for laboratory data will lead to faster patient discharges and a reduction in overall hospital costs. The NACB Committee encourages prospective outcome studies to examine the putative advantage of reporting TATs within 1 h.
Recommendations: Institutions that cannot consistently deliver cardiac marker TATs of ~1 h should implement POC testing devices. The cutoff concentrations of these devices should be set at the 97.5% upper reference limits so that the devices can detect the first presence of true myocardial injury.
Strength/consensus of recommendation: Class I.
recommendation 4
POC devices are designed for testing to be performed at
or near the bedside by the primary caregivers. However, the
responsibility for this testing must reside with the laboratory. The
success of POC testing programs will depend on cooperation and the
acknowledgment of the laboratory’s responsibility by hospital
administrations, nursing staffs, and the appropriate units within the
hospital (e.g., the ED).
When the laboratory staff recognizes a situation of noncompliance, they should have the authority to remove POC testing devices and suspend testing from the area of the hospital where the testing was conducted until the deficiencies have been satisfactorily corrected.
Recommendation: Among other tasks, laboratory personnel must be involved in the selection of devices, the training of individuals to perform the analysis, the maintenance of POC equipment, the verification of the proficiency of operators on a regular basis, and the compliance of documentation with requirements by regulatory agencies such as the Health Care Finance Administration and the Clinical Laboratory Improvement Act of 1988. In meeting these requirements, quality-assurance and quality-control programs must be instituted and fully documented on a regular basis.
Strength/consensus of recommendation: Class I.
recommendation 5
Assays for cardiac markers for early diagnosis, rule-out, triaging
of patients from the ED, or for determination of successful reperfusion
require markers that have a short assay TAT. Irrespective of how the
testing is performed (i.e., laboratory-based or POC testing), assays
must meet minimum precision requirements. Imprecise assays at or near
cutoff concentrations will adversely affect the clinical performance of
the
test.
The NACB Committee understands the importance of establishing objective analytical goals for assays for new cardiac markers. This will assist manufacturers in the construction of new assays. The total precision required for a particular assay is dependent on the biological variation of the analyte. The biologic variation has been established at <5.6% for myoglobin (116) and <9.3% for CK-MB (117). The biologic variation for cardiac troponin has not been established. As such, this recommendation for total precision was arbitrarily set at 10% without a prior scientific basis.
<2>Recommendation: Assays for cardiac markers should have an imprecision (CV) <10% at the AMI decision limits and an assay TAT of <30 min. Before launch, assays must be characterized with respect to potentially interfering substances [e.g., other related proteins, human anti-mouse antibodies (114)(115), and other interferences].
Strength/consensus of recommendation: Class II.
recommendation 6
Most patients with cardiac diseases are heparinized while
hospitalized. When serum is collected from these patients, full clot
retraction from tubes without preservatives can take 10–15 min or
more. Clots can continue to form even after the sample has been
centrifuged and the serum placed onto immunoassay analyzers. When this
occurs, instrument probes can be blocked by fibrinous material. For
automated immunoassay analysis, the use of plasma will eliminate the
extra time needed for clotting, thereby reducing the overall
preanalytical TATs. Manufacturers should target their assays for use in
plasma. Results for serum and plasma are not interchangeable for all
assays and markers, particularly for cTnI. Therefore, for cardiac
troponin, NACB cannot recommend that laboratories intermix different
types of blood collection tubes at the same
facility.
Although whole blood testing is not an option for most automated immunoassay analyzers, it is available for POC testing. The use of whole blood can reduce assay and reporting TATs. Currently, the assay TATs for myoglobin, CK-MB, and troponin are 10–20 min. For some samples, dilutions will be necessary to report quantitative results that are within the limits of the reportable range. Electronic transmission of results will be essential for efficient delivery of results.
Recommendation: Plasma or anticoagulated whole blood are the specimens of choice for the stat analysis of cardiac markers.
Strength/consensus of recommendation: Class I.
Discussion.
In the original draft of the Guidelines, the
recommendation stated that heparinized plasma is the specimen of choice
for troponin measurements. However, some reviewers, particularly those
in Europe, suggested that the Guidelines be expanded to included all
forms of plasma collection tubes (such as EDTA or citrated collection
tubes). Laboratories that choose to use these collection types must
proceed with caution. With EDTA tubes, troponin released as a ternary
(cTnT-I-C) or binary (cTnI-C) complex will degrade to free subunits
because ionized calcium is needed to maintain this complex and is
removed by chelation of the metal ions (118) Troponin assays
that do not exhibit an equimolar response between complexed and free
subunits will produce significant biases between serum and EDTA plasma
(97). Heparin does not disrupt complexes; therefore, no
change in results between serum and plasmas are expected. The
laboratory must follow the recommendations for acceptable specimen
types listed in manufacturers’ package inserts and should use a
reference interval specific to the specimen type.
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General Discussion |
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TopAbstractSession I. Recommendations for...Session II. Recommendations for...Session III. Recommendations for...Session IV. Recommendations for...General DiscussionReferences |
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The objective of the NACB Committee was not to make recommendations as to how cardiac markers are to be used with other diagnostic modalities (e.g., electrocardiography, echocardiography, and nuclear imaging ventriculography) or how results should be used to select specific therapies. Organizations such as the National Heart Attack Alert Program Committee and the Agency for Health Care Policy Research have been developed to address such issues.
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Acknowledgments |
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Footnotes |
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Mauro Panteghini, Brescia, Italy (Chair) and Francesco Dati, DiaSys Diagnostics, Holzheim, Germany (Committee member) also participated in discussions of these recommendations as members of the International Federation of Clinical Chemistry Committee for the Standardization of Markers of Cardiac Damage. A list of conference participants, reviewers, and corporate sponsors will be available with the National Academy of Clinical Biochemistry monograph.
1 Nonstandard abbreviations: NACB, National Academy of Clinical Biochemistry; ED, emergency department; AMI, acute myocardial infarction; CK and CK-MB, creatine kinase and CK MB isoenzyme; cTnT and cTnI, cardiac troponins T and I; POC, point-of-care; TIMI, Thrombolysis in Myocardial Infarction; and TAT, turnaround time. 
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NACB WRITING GROUP MEMBERS, F. S. Apple, R. L. Jesse, L. K. Newby, A. H.B. Wu, R. H. Christenson, NACB COMMITTEE MEMBERS, R. H. Christenson, F. S. Apple, C. P. Cannon, et al. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biochemical Markers of Acute Coronary Syndromes Clin. Chem., April 1, 2007; 53(4): 547 - 551. [Full Text] [PDF]
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N. Nagajothi and A. Trivedi Biomarkers in Acute Cardiac Disease J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2358 - 2358. [Full Text] [PDF]
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A. S. Jaffe, L. Babuin, and F. S. Apple Reply J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2358 - 2359. [Full Text] [PDF]
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T. G. Neilan, J. L. Januzzi, E. Lee-Lewandrowski, T.-T. Ton-Nu, D. M. Yoerger, D. S. Jassal, K. B. Lewandrowski, A. J. Siegel, J. E. Marshall, P. S. Douglas, et al. Myocardial Injury and Ventricular Dysfunction Related to Training Levels Among Nonelite Participants in the Boston Marathon Circulation, November 28, 2006; 114(22): 2325 - 2333. [Abstract] [Full Text] [PDF]
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P. A. Kavsak, A. R. MacRae, G. E. Palomaki, A. M. Newman, D. T. Ko, V. Lustig, J. V. Tu, and A. S. Jaffe Health Outcomes Categorized by Current and Previous Definitions of Acute Myocardial Infarction in an Unselected Cohort of Troponin-Naive Emergency Department Patients Clin. Chem., November 1, 2006; 52(11): 2028 - 2035. [Abstract] [Full Text] [PDF]
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 A. O. Adesanya, J. A. de Lemos, N. B. Greilich, and C. W. Whitten Management of perioperative myocardial infarction in noncardiac surgical patients. Chest, August 1, 2006; 130(2): 584 - 596. [Abstract] [Full Text] [PDF]
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W. L. Miller, K. N. Garratt, M. F. Burritt, R. J. Lennon, G. S. Reeder, and A. S. Jaffe Baseline troponin level: key to understanding the importance of post-PCI troponin elevations Eur. Heart J., May 1, 2006; 27(9): 1061 - 1069. [Abstract] [Full Text] [PDF]
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A. R. MacRae, P. A. Kavsak, V. Lustig, R. Bhargava, R. Vandersluis, G. E. Palomaki, M.-J. Yerna, and A. S. Jaffe Assessing the Requirement for the 6-Hour Interval between Specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies Clin. Chem., May 1, 2006; 52(5): 812 - 818. [Abstract] [Full Text] [PDF]
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 P O Collinson, D C Gaze, K Bainbridge, F Morris, B Morris, A Price, and S Goodacre Utility of admission cardiac troponin and "Ischemia Modified Albumin" measurements for rapid evaluation and rule out of suspected acute myocardial infarction in the emergency department. Emerg. Med. J., April 1, 2006; 23(4): 256 - 261. [Abstract] [Full Text] [PDF]
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F. S. Apple, R. Ler, A. Y. Chung, M. J. Berger, and M. M. Murakami Point-of-Care i-STAT Cardiac Troponin I for Assessment of Patients with Symptoms Suggestive of Acute Coronary Syndrome, Clin. Chem., February 1, 2006; 52(2): 322 - 325. [Abstract] [Full Text] [PDF]
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K. Rajappan, E. Murphy, V. Amber, F. Meakin, B. Muller, K.F. Fox, and C.S.R. Baker Usage of troponin in the real world: a lesson for the introduction of biochemical assays QJM, May 1, 2005; 98(5): 337 - 342. [Abstract] [Full Text] [PDF]
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S. Eriksson, T. Ilva, C. Becker, J. Lund, P. Porela, K. Pulkki, L.-M. Voipio-Pulkki, and K. Pettersson Comparison of Cardiac Troponin I Immunoassays Variably Affected by Circulating Autoantibodies Clin. Chem., May 1, 2005; 51(5): 848 - 855. [Abstract] [Full Text] [PDF]
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S. Eriksson, H. Halenius, K. Pulkki, J. Hellman, and K. Pettersson Negative Interference in Cardiac Troponin I Immunoassays by Circulating Troponin Autoantibodies Clin. Chem., May 1, 2005; 51(5): 839 - 847. [Abstract] [Full Text] [PDF]
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F. S. Apple, A. H.B. Wu, J. Mair, J. Ravkilde, M. Panteghini, J. Tate, F. Pagani, R. H. Christenson, M. Mockel, O. Danne, et al. Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome Clin. Chem., May 1, 2005; 51(5): 810 - 824. [Abstract] [Full Text] [PDF]
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G. Cook, D. Taylor, M. France, G. Burrows, E. Manning, G. Lyratzopoulos, P. McElduff, P. Lewis, M. Martin, and R.F. Heller Survival among hospital in-patients with troponin T elevation below levels defining myocardial infarction QJM, April 1, 2005; 98(4): 275 - 282. [Abstract] [Full Text] [PDF]
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R. Rej Clinical Chemistry through Clinical Chemistry: A Journal Timeline Clin. Chem., December 1, 2004; 50(12): 2415 - 2458. [Abstract] [Full Text] [PDF]
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M. Panteghini Role and importance of biochemical markers in clinical cardiology Eur. Heart J., July 2, 2004; 25(14): 1187 - 1196. [Abstract] [Full Text] [PDF]
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M. C. Kontos, R. Shah, L. M. Fritz, F. P. Anderson, J. L. Tatum, J. P. Ornato, and R. L. Jesse Implication of different cardiac troponin I levels for clinical outcomes and prognosis of acute chest pain patients J. Am. Coll. Cardiol., March 17, 2004; 43(6): 958 - 965. [Abstract] [Full Text] [PDF]
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A. Elsaesser and C. W. Hamm Acute Coronary Syndrome: The Risk of Being Female Circulation, February 10, 2004; 109(5): 565 - 567. [Full Text] [PDF]
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M. Panteghini, F. Pagani, K.-T. J. Yeo, F. S. Apple, R. H. Christenson, F. Dati, J. Mair, J. Ravkilde, and A. H.B. Wu Evaluation of Imprecision for Cardiac Troponin Assays at Low-Range Concentrations Clin. Chem., February 1, 2004; 50(2): 327 - 332. [Abstract] [Full Text] [PDF]
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J. C. Lin, F. S. Apple, M. M. Murakami, and R. V. Luepker Rates of Positive Cardiac Troponin I and Creatine Kinase MB Mass among Patients Hospitalized for Suspected Acute Coronary Syndromes Clin. Chem., February 1, 2004; 50(2): 333 - 338. [Abstract] [Full Text] [PDF]
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W. L. Miller, K. N. Garratt, M. F. Burritt, G. S. Reeder, and A. S. Jaffe Timing of Peak Troponin T and Creatine Kinase-MB Elevations After Percutaneous Coronary Intervention Chest, January 1, 2004; 125(1): 275 - 280. [Abstract] [Full Text] [PDF]
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F. S. Apple, H. E. Quist, P. J. Doyle, A. P. Otto, and M. M. Murakami Plasma 99th Percentile Reference Limits for Cardiac Troponin and Creatine Kinase MB Mass for Use with European Society of Cardiology/American College of Cardiology Consensus Recommendations Clin. Chem., August 1, 2003; 49(8): 1331 - 1336. [Abstract] [Full Text] [PDF]
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S. Eriksson, M. Junikka, P. Laitinen, K. Majamaa-Voltti, H. Alfthan, and K. Pettersson Negative Interference in Cardiac Troponin I Immunoassays from a Frequently Occurring Serum and Plasma Component Clin. Chem., July 1, 2003; 49(7): 1095 - 1104. [Abstract] [Full Text] [PDF]
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P. Venge, N. Johnston, B. Lagerqvist, L. Wallentin, and B. Lindahl Clinical and Analytical Performance of the Liaison Cardiac Troponin I Assay in Unstable Coronary Artery Disease, and the Impact of Age on the Definition of Reference Limits. A FRISC-II Substudy Clin. Chem., June 1, 2003; 49(6): 880 - 886. [Abstract] [Full Text] [PDF]
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M. Herrmann, J. Scharhag, M. Miclea, A. Urhausen, W. Herrmann, and W. Kindermann Post-Race Kinetics of Cardiac Troponin T and I and N-Terminal Pro-Brain Natriuretic Peptide in Marathon Runners Clin. Chem., May 1, 2003; 49(5): 831 - 834. [Full Text] [PDF]
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M. E. Bertrand, M. L. Simoons, K. A.A. Fox, L. C. Wallentin, C. W. Hamm, E. McFadden, P. J. De Feyter, G. Specchia, and W. Ruzyllo Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Eur. Heart J., December 1, 2002; 23(23): 1809 - 1840. [Full Text] [PDF]
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J. R. Tate, T. Badrick, G. Koumantakis, J. M. Potter, and P. E. Hickman Reporting of Cardiac Troponin Concentrations Clin. Chem., November 1, 2002; 48(11): 2077 - 2080. [Full Text] [PDF]
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L. J. Kim, E. A. Martinez, N. Faraday, T. Dorman, L. A. Fleisher, B. A. Perler, G. M. Williams, D. Chan, and P. J. Pronovost Cardiac Troponin I Predicts Short-Term Mortality in Vascular Surgery Patients Circulation, October 29, 2002; 106(18): 2366 - 2371. [Abstract] [Full Text] [PDF]
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M. Panteghini Acute Coronary Syndrome: Biochemical Strategies in the Troponin Era Chest, October 1, 2002; 122(4): 1428 - 1435. [Abstract] [Full Text] [PDF]
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F. S. Apple, M. M. Murakami, R. L. Jesse, M. A. Levitt, A. K. Berger, L. A. Pearce, and P. Collinson Near-Bedside Whole-Blood Cardiac Troponin I Assay for Risk Assessment of Patients with Acute Coronary Syndromes Clin. Chem., October 1, 2002; 48(10): 1784 - 1787. [Full Text] [PDF]
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M. Panteghini, C. Cuccia, G. Bonetti, R. Giubbini, F. Pagani, and E. Bonini Single-Point Cardiac Troponin T at Coronary Care Unit Discharge after Myocardial Infarction Correlates with Infarct Size and Ejection Fraction Clin. Chem., September 1, 2002; 48(9): 1432 - 1436. [Abstract] [Full Text] [PDF]
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W. J. Kim, O. F. Laterza, K. G. Hock, J. F. Pierson-Perry, D. M. Kaminski, M. Mesguich, F. Braconnier, R. Zimmermann, M. Zaninotto, M. Plebani, et al. Performance of a Revised Cardiac Troponin Method That Minimizes Interferences from Heterophilic Antibodies Clin. Chem., July 1, 2002; 48(7): 1028 - 1034. [Abstract] [Full Text] [PDF]
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F. S. Apple, H. E. Quist, A. P. Otto, W. E. Mathews, and M. M. Murakami Release Characteristics of Cardiac Biomarkers and Ischemia-modified Albumin as Measured by the Albumin Cobalt-binding Test after a Marathon Race Clin. Chem., July 1, 2002; 48(7): 1097 - 1100. [Full Text] [PDF]
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D. Peetz, G. Hafner, and K. J. Lackner Analytical Characteristics of the AxSYM Cardiac Troponin I and Creatine Kinase MB Assays Clin. Chem., July 1, 2002; 48(7): 1110 - 1111. [Full Text] [PDF]
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A. H.B. Wu, R. Valdes Jr, and C. D. Hawker Guidelines and Recommendations in Laboratory Medicine Clin. Chem., July 1, 2002; 48(7): 1135 - 1136. [Full Text] [PDF]
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E. M. Antman Decision Making with Cardiac Troponin Tests N. Engl. J. Med., June 27, 2002; 346(26): 2079 - 2082. [Full Text] [PDF]
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D. Uettwiller-Geiger, A. H.B. Wu, F. S. Apple, A. W. Jevans, P. Venge, M. D. Olson, C. Darte, D. L. Woodrum, S. Roberts, and S. Chan Multicenter Evaluation of an Automated Assay for Troponin I Clin. Chem., June 1, 2002; 48(6): 869 - 876. [Abstract] [Full Text] [PDF]
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A. Cerutti, L. Corsini, R. Finotto, and C. Perazzi Comparison of Cardiac Troponin I in Serum and Heparin Plasma with the Dimension RxL Assay Clin. Chem., May 1, 2002; 48(5): 790 - 791. [Full Text] [PDF]
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F. S. Apple, A. S. Jaffe, L. K. Newby, A. L. Kaplan, R. H. Tuttle, S. E. McNulty, E. M. Ohman, A. B. Storrow, W. B. Gibler, J. L. Garvey, et al. Bedside Multimarker Testing for Risk Stratification in Chest Pain Units: The Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin, and Troponin I (CHECKMATE) Study Response Circulation, November 27, 2001; 104 (22): e125 - e126. [Full Text] [PDF]
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F. S. Apple and A. H.B. Wu Myocardial Infarction Redefined: Role of Cardiac Troponin Testing Clin. Chem., March 1, 2001; 47(3): 377 - 379. [Full Text] [PDF]
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J. C.J.M. Swaanenburg, B. G. Loef, M. Volmer, P. W. Boonstra, J. G. Grandjean, M. A. Mariani, and A. H. Epema Creatine Kinase MB, Troponin I, and Troponin T Release Patterns after Coronary Artery Bypass Grafting with or without Cardiopulmonary Bypass and after Aortic and Mitral Valve Surgery Clin. Chem., March 1, 2001; 47(3): 584 - 587. [Full Text] [PDF]
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R Bholasingh, R J de Winter, J C Fischer, R W Koster, R J G Peters, and G T Sanders Safe discharge from the cardiac emergency room with a rapid rule-out myocardial infarction protocol using serial CK-MBmass Heart, February 1, 2001; 85(2): 143 - 148. [Abstract] [Full Text]
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J. L. McDonough, R. Labugger, W. Pickett, M. Y. Tse, S. MacKenzie, S. C. Pang, D. Atar, G. Ropchan, and J. E. Van Eyk Cardiac Troponin I Is Modified in the Myocardium of Bypass Patients Circulation, January 2, 2001; 103(1): 58 - 64. [Abstract] [Full Text] [PDF]
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D. A. Morrow, E. M. Antman, M. Tanasijevic, N. Rifai, J. A. de Lemos, C. H. McCabe, C. P. Cannon, and E. Braunwald Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-11B substudy J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1812 - 1817. [Abstract] [Full Text] [PDF]
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M. C. Kontos, F. P. Anderson, R. Alimard, J. P. Ornato, J. L. Tatum, and R. L. Jesse Ability of troponin I to predict cardiac events in patients admitted from the emergency department J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1818 - 1823. [Abstract] [Full Text] [PDF]
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R. J. de Winter Risk stratification with cardiac troponin I in acute coronary syndromes J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1824 - 1826. [Full Text] [PDF]
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F. S. Apple, F. P. Anderson, P. Collinson, R. L. Jesse, M. C. Kontos, M. A. Levitt, E. A. Miller, and M. M. Murakami Clinical Evaluation of the First Medical Whole Blood, Point-of-Care Testing Device for Detection of Myocardial Infarction Clin. Chem., October 1, 2000; 46(10): 1604 - 1609. [Abstract] [Full Text] [PDF]
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M. Zaninotto, F. Pagani, S. Altinier, P. Amboni, R. Bonora, A. Dolci, P. Pergolini, A. Vernocchi, M. Plebani, M. Panteghini, et al. Multicenter Evaluation of Five Assays for Myoglobin Determination Clin. Chem., October 1, 2000; 46(10): 1631 - 1637. [Abstract] [Full Text] [PDF]
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A. S. Jaffe, J. Ravkilde, R. Roberts, U. Naslund, F. S. Apple, M. Galvani, and H. Katus It's Time for a Change to a Troponin Standard Circulation, September 12, 2000; 102(11): 1216 - 1220. [Full Text] [PDF]
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Myocardial Myocardial infarction redefined--A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction Eur. Heart J., September 2, 2000; 21(18): 1502 - 1513. [Abstract] [PDF]
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E. Braunwald, E. M. Antman, J. W. Beasley, R. M. Califf, M. D. Cheitlin, J. S. Hochman, R. H. Jones, D. Kereiakes, J. Kupersmith, T. N. Levin, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina) J. Am. Coll. Cardiol., September 1, 2000; 36(3): 970 - 1062. [Full Text] [PDF]
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H. Stiegler, Y. Fischer, J. F. Vazquez-Jimenez, J. Graf, K. Filzmaier, B. Fausten, U. Janssens, A. M. Gressner, and D. Kunz Lower Cardiac Troponin T and I Results in Heparin-Plasma Than in Serum Clin. Chem., September 1, 2000; 46(9): 1338 - 1344. [Abstract] [Full Text] [PDF]
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S. Altinier, M. Mion, A. Cappelletti, M. Zaninotto, and M. Plebani Rapid Measurement of Cardiac Markers on Stratus CS Clin. Chem., July 1, 2000; 46(7): 991 - 993. [Full Text] [PDF]
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F. Pagani, G. Bonetti, F. Stefini, C. Cuccia, M. Panteghini, B. Bluestein, B. Markham, and D. Waskiewicz Serum and Plasma Samples for ACS:Systems Cardiac Markers Representatives of the manufacturer respond: Clin. Chem., July 1, 2000; 46(7): 1020 - 1022. [Full Text] [PDF]
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W. Gerhardt, G. Nordin, A.-K. Herbert, B. Linaker Burzell, A. Isaksson, E. Gustavsson, S. Haglund, M. Muller-Bardorff, and H. A. Katus Troponin T and I Assays Show Decreased Concentrations in Heparin Plasma Compared with Serum: Lower Recoveries in Early than in Late Phases of Myocardial Injury Clin. Chem., June 1, 2000; 46(6): 817 - 821. [Abstract] [Full Text] [PDF]
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L.-M. Voipio-Pulkki, P. Porela, H. Helenius, and K. Pulkki A reply Eur. Heart J., May 2, 2000; 21(10): 858 - 858. [PDF]
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J. Ravkilde Risk Stratification in Acute Coronary Syndrome Using Cardiac Troponin I Clin. Chem., April 1, 2000; 46(4): 443 - 444. [Full Text] [PDF]
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D. A. Morrow, N. Rifai, M. J. Tanasijevic, D. R. Wybenga, J. A. de Lemos, and E. M. Antman Clinical Efficacy of Three Assays for Cardiac Troponin I for Risk Stratification in Acute Coronary Syndromes: A Thrombolysis In Myocardial Infarction (TIMI) 11B Substudy Clin. Chem., April 1, 2000; 46(4): 453 - 460. [Abstract] [Full Text] [PDF]
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G. A. Ewy and J. P. Ornato Emergency cardiac care: introduction J. Am. Coll. Cardiol., March 15, 2000; 35(4): 825 - 880. [Full Text] [PDF]
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