Download Detection of Myocardial Infarction—Is It All

Point/Counterpoint
Clinical Chemistry 58:1
158–161 (2012)
- POINT -
Detection of Myocardial Infarction—Is It All Troponin?
Evangelos Giannitsis1 and Hugo A. Katus1*
Cardiac troponin is a cardiospecific protein that is detectable in the blood of patients with myocardial injury
with sensitive and specific assays (1 ). Cardiac troponin
is recommended as the preferred biomarker for the diagnosis of myocardial infarction (MI),2 for risk stratification, and for therapeutic guidance regarding anticoagulation therapy and invasive management (2– 4 ).
Assays should be appropriately precise to measure at
the 99th-percentile value with a total imprecision of
ⱕ10%. Until recently, assays were insufficiently precise, and rather than using the recommended 99thpercentile value, many clinicians had advocated the use
of the lowest value at which an assay achieved a 10% CV
as the decision cutoff. Manufacturers have refined their
assays through improvements in reagent or antibody
configuration, changes in the microparticle capture
bed, introduction of a third antibody, increases in sample volume, and other modifications (5 ). For these reasons, newer generations of cardiac troponin assays now
provide improved analytical sensitivity and precision.
High-sensitivity cardiac troponin assays have reduced the time from symptom onset to detectable
marker increases compared with former assays. Keller
et al. (6 ) demonstrated that a contemporary sensitive
cardiac troponin I (cTnI) assay allowed a diagnosis of
MI on admission in an acute coronary syndrome
(ACS) population with a sensitivity of 90.7% and a
negative predictive value (NPV) of 96.4%. A second
sample 3 h after symptom onset identified all patients
with a final MI diagnosis, irrespective of the time delay
from onset of symptoms to presentation. Reichlin et al.
(7 ) evaluated 786 consecutive patients with suspected
ACS and demonstrated better performance of 4 cardiac
troponin assays more sensitive than the conventional
1
Medizinische Klinik, Abteilung für Innere Medizin III, Universitätsklinikum
Heidelberg, Heidelberg, Germany.
* Address correspondence to this author at: Medizinische Klinik III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Fax ⫹49-6221-56-5516; e-mail
[email protected].
Received June 28, 2011; accepted October 28, 2011.
Previously published online at DOI: 10.1373/clinchem.2011.168575
2
Nonstandard abbreviations: MI, myocardial infarction; cTnI, cardiac troponin I;
ACS, acute coronary syndrome; NPV, negative predictive value; STEMI, STelevation MI; hs-cTnT, high-sensitivity cardiac troponin T (assay); MERLIN-TIMI,
Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation
Acute Coronary Syndromes (trial); AMI, acute MI; PLATO, Platelet Inhibition and
Patient Outcomes (trial); PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition (trial).
158
fourth-generation cTnT assay, with sensitivities at presentation of between 84% and 95% (NPVs, 97%–
99%). Both trials indicated that the benefits of earlier
detection were most pronounced for patients presenting early after chest pain onset (6, 7 ).
There is debate regarding the usefulness of additional
biomarkers for detecting myocardial necrosis before measurable increases in cardiac troponin concentrations occur in the blood. Kurz et al. (8 ) provided evidence that use
of a high-sensitivity assay to measure cTnT in admission
samples proved at least as effective for predicting non–STelevation MI (non-STEMI) as measuring myoglobin or
heart-type fatty acid– binding protein. Whether copeptin,
a stable fragment of vasopressin that is rapidly released
into the blood after life-threatening stress or hemodynamic compromise and returns to normal within a few
hours, will add to the excellent NPV of cTnT measured
with the high-sensitivity cTnT (hs-cTnT) assay is unclear.
Given a reported NPV of ⬎99% for the combination of
cTnT measured by the fourth-generation cTnT assay and
copeptin, this strategy is interesting for rapidly and safely
ruling out non-STEMI from the initial blood draw in order to optimize the triage of patients in busy chest pain
units or emergency departments and to avoid prolonged
observation times or unnecessary hospitalizations (9 ).
Precision is not the only variable useful in evaluating assays. There are differences related to the analytical performance of high-sensitivity cardiac troponin
assays (10 ). Assays may be configured to provide improved imprecision by increasing the threshold of the
assay, but this improvement comes at the expense of a
decrease in diagnostic sensitivity. To address this issue,
Apple proposed a scorecard grading system that considers both precision and analytical sensitivity (10 ).
Whether differences related to analytical performance
have an effect on clinical performance is still unclear.
Reichlin et al. (7 ) tested 4 sensitive assays and reported
comparable performance; all of the assays outperformed the fourth-generation cTnT assay that served
as the reference. In contrast, unpublished findings
from our group for 1386 patients with suspected ACS
indicate a superior prognostic performance for the hscTnT assay (Fig. 1), compared with a contemporary
sensitive cTnI assay (Siemens Ultra). Several preanalytical factors have also been reported to interfere with
cardiac troponin measurements, particularly at low
concentrations. These factors include cross-reactivity
Point/Counterpoint
Fig. 1. Impact of contemporary and high-sensitivity cardiac troponin assay results on outcomes.
Values less than and greater or equal to the 99th-percentile are indicated by plus signs and minus signs, respectively. Indicated
are rates of all-cause death and MI (left panel) and all-cause death (right panel) within 3 years.
with heterophilic antibodies and autoantibodies, as
well as severe hemolysis. Each of these factors can cause
either overestimation or underestimation of cardiac
troponin concentrations (11 ). For some, but not for
all, assays (12 ), the use of different cutoff values for
men and women may also be necessary.
The use of biomarkers is not recommended for
STEMI diagnosis, because it is based on electrocardiogram evidence. High-sensitivity cardiac troponin
assays will facilitate the detection of all other nonSTEMIs, including so-called microinfarcts. Application of the diagnostic criteria of the ESC/ACCF/AHA/
WHF Task Force for infarct definition (3 ) will have a
major impact on the numbers of non-STEMI diagnoses. Lowering the diagnostic threshold to the 99thpercentile value will decrease the numbers of patients
with unstable angina and proportionately increase the
number ruling in for non-STEMI (5 ). This reclassification of ACS patients is not a simple change in the
prevalence of unstable angina and non-STEMI, but it is
of high clinical relevance, because even minor increases
in cardiac troponin above the 99th-percentile value are
associated with adverse short- and long-term outcomes. The MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST
Elevation Acute Coronary Syndromes), a large-scale
trial of 4513 patients with ACS, demonstrated a 3-fold
higher adjusted risk of death and recurrent MI at 30
days and a 2.7-fold higher risk at 12 months, when cTnI
values exceeded the 99th percentile (13 ). The low residual risk for adverse short- and long-term outcomes
in chest pain patients who show no increase in cardiac
troponin to ⱖ99th percentile is equally important. It
appears that these patients have much better outcomes
and do not derive benefit from aggressive diagnostic
and therapeutic procedures, observations that prompt
one to ask whether these patients should be labeled as
having ACS.
It is very likely that the use of hs-cTnT and hs-cTnI
assays will improve early rule in and rule out of suspected MI and will allow a more accurate and sensitive
diagnosis of MI; however, the use of such assays requires scrutiny and a high level of professional experience for proper interpretation. The higher proportion
of increased cardiac troponin in asymptomatic and
symptomatic patients not due to acute MI (AMI) has
started to confuse physicians. The term “false-positive
cardiac troponin result” should be used cautiously for
patients without clinical proof of AMI. As may be expected, lowering a test’s diagnostic threshold will inherently increase the diagnostic sensitivity for myocardial injury but decrease the diagnostic specificity for MI
(14 ). When increased cardiac troponin values are encountered in the absence of myocardial ischemia, a
careful search for other possible etiologies of cardiac
damage should be undertaken, because an increased
high-sensitivity cardiac troponin value is associated
with an adverse prognosis in almost all situations.
Overdiagnosis of MI, workup bias, and overtreatment
can be avoided with simple measures, including a strict
adherence to the clinical definition of MI and consideration of kinetic changes. Although increased cardiac
troponin results with conventional assays usually have
meant sending patients to the catheterization laboratory, the results of high-sensitivity cardiac troponin assays require scrutiny and clinical experience for proper
interpretation.
Whether there is a distinct cardiac troponin
threshold that is helpful for guiding anticoagulation
treatment or selecting patients who will derive benefit
Clinical Chemistry 58:1 (2012) 159
Point/Counterpoint
from early coronary angiography is as yet unclear. Cardiac troponin results from the large prospective
PLATO (Platelet Inhibition and Patient Outcomes)
trial (15 ) evaluating the effects of ticagrelor, a novel
direct-acting reversible ADP receptor inhibitor, are expected to be published soon. Cardiac troponin concentrations were measured with conventional, contemporary sensitive, and high-sensitivity cardiac troponin
assays in ⬎18 000 patients with non–ST-elevation ACS
and STEMI who received ticagrelor or clopidogrel
and underwent medical, interventional, or surgical
treatment.
According to the universal definition, AMI is defined by an increasing and/or decreasing pattern of cardiac troponin concentrations, with at least 1 value
above the 99th percentile in the setting of a patient with
clinical features of myocardial ischemia (3 ). The interpretation of changes (␦ values) cannot be done in isolation from the clinical situation and requires consideration of several variables that influence the slope and
pattern (increase or decrease). These variables include
time from the onset of chest pain to cardiac troponin
testing and reperfusion success. In addition, the definition requires serial sampling with an appropriately
timed interval between at least 2 consecutive blood
draws and the point in time from the onset of symptoms to account for the time-dependent kinetic
changes in AMI and other acute or chronic injuries of
the heart. The magnitude of the concentration change
that best discriminates between acute and chronic increases has not been defined yet, and it is still a matter
of debate whether one should prefer relative changes,
absolute changes, or the reference change value, a metric calculated from short-term or intermediate-term
biological variation in cardiac troponin.
Considering future perspectives, the number of
indications for testing of cardiac troponin in settings
other than ACS will increase. The PEACE (Prevention
of Events with Angiotensin Converting Enzyme Inhibition) study of 3679 patients with stable coronary artery disease and a preserved left ventricular function
demonstrated that small increases in cTnT measured
with the hs-cTnT assay were associated with a higher
risk of death and rehospitalization for heart failure
(16 ). Our group demonstrated an association between
cTnT concentrations (measured with the hs-cTnT assay) and the presence and composition of coronary
plaque detected with multislice coronary computed tomography (17 ). These observations suggest that highsensitivity cardiac troponin assays should be incorporated into the routine clinical workup of patients with
stable coronary artery disease. Furthermore, the Dallas
Heart Study found that increases in cardiac troponin
are seen more frequently with the hs-cTnT assay in
noncoronary heart disease (18 ). Given that an in160 Clinical Chemistry 58:1 (2012)
creased cardiac troponin concentration is almost always associated with an adverse prognosis (19 ), regardless of whether the underlying cause is acute or
chronic, measurement of cardiac troponin with highsensitivity assays should be considered for risk stratification in cases of acute or chronic heart disease, because previous reports have suggested a performance
similar to that of natriuretic peptides, heart-type fatty
acid– binding protein, or growth differentiation factor
15 (20 ).
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential
Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: E. Giannitsis, Roche Diagnostics; H.A.
Katus, Roche Diagnostics.
Stock Ownership: None declared.
Honoraria: E. Giannitsis, Roche Diagnostics; H.A. Katus, Roche
Diagnostics.
Research Funding: None declared.
Expert Testimony: None declared.
Other Remuneration: H.A. Katus developed the cTnT assay and
holds a patent jointly with Roche Diagnostics.
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Point/Counterpoint
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