Cardiac biomarkers and acute coronary syndromes — The Euro Heart Survey of Acute Coronary Syndromes Experience

David Hasdaia,*, Solomon Beharb, Valentina Boykob, Nicholas Danchinc, Jean-Pierre Bassandd and Alexander Battlera

a Rabin Medical Center, Petah Tikva, Israel
b Neufeld Cardiac Research Institute, Tel Hashomer, Israel
c Hôpital Européen Georges Pompidou, Paris, France
d University Hospital Jean-Minjoz, Besancon, France

* Correspondence to: David Hasdai, MD. Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St. Petah Tikva, Israel 49100. Tel: 972-3-9377130. Fax: 972-3-9249850
E-mail address: dhasdai{at}post.tau.ac.il

Received 22 November 2002; revised 4 March 2003; accepted 12 March 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims To examine the application of the redefinition of acute myocardial infarction (AMI) published on 4 September 2000.

Methods and results The Euro Heart Survey of Acute Coronary Syndromes (ACS) prospectively surveyed 10484 patients in 103 hospitals across 25 European and Mediterranean basin countries during 4 September 2000 to 15 May 2001. We evaluated the use of cardiac troponin assays and whether the diagnosis of unstable angina (UA) or AMI was in accordance with the results of biomarker assays (cardiac troponins, CK-MB mass, CK-MB%, or CK). Troponin assays were used in 6036 (63.3%) of the 9538 patients with available biomarker levels; of whom elevated troponin levels were recorded in 648 of 2307 (28.1%) patients with UA and in 2957 of 3729 (79.3%) patients with AMI. Of the 8871 patients with available creatine kinase values, levels above the upper limit of normal were recorded in 848 of 3625 (23.4%) patients with UA and in 3948 of 5246 (75.3%) patients with AMI.

Conclusions Cardiac troponin assays are still not universally available for the evaluation of ACS patients. A substantial proportion of ACS patients receive a diagnosis of UA or AMI, irrespective of the result of biomarker assays, indicating that the redefinition of AMI has not yet been universally adopted, and that additional efforts are warranted to ensure its appropriate implementation.

Key Words: Acute myocardial infarction • Acute coronarysyndrome • Diagnosis • Biomarker • Troponin • Creatine kinase


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
On 4 September 2000 the European Society of Cardiology and the American College of Cardiology issued a joint consensus document, redefining acute myocardial infarction (AMI).1The new definition of AMI emphasizes the role of more sensitive and specific serologic biomarkers of myocardial necrosis, in particular the cardiac troponins. Thus, the diagnosis of acute, evolving, or recent AMI, based on the new definition of AMI, primarily relies on the typical rise and fall of biochemical markers of myocardial necrosis. Given the higher sensitivity of the newer biomarkers for myocardial necrosis, in particular the cardiac troponins, a substantial proportion of patients who had previously been considered as having had myocardial ischaemia are now considered to have had AMI.

The joint committee redefining AMI emphasized that efforts should be exerted to examine whether the measures generating the new criteria, namely the cardiac troponin assays, are widespread available and applied in a standard fashion.1Moreover, the committee recommended an examination of its application over time.

The Euro Heart Survey of Acute CoronarySyndromes (Euro Heart Survey ACS) was a prospective survey of patients admitted due to an ACS in 103 hospitals across 25 countries in Europe and the Mediterranean basin.2The enrolment period was from 4 September 2000. Thus, this survey offers a unique opportunity to examine the application of the new definition of AMI across this broad region.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Euro Heart Survey ACS
The details of the Euro Heart Survey ACS have been previously described in detail.2The survey was performed in clusters composed of academic and non-academic hospitals and hospitals with and without cardiac catheterisation laboratories and cardiac surgery facilities. The enrolment period was from 4 September 2000 to 15 May 2001.

All patients with suspected ACS, screened at the emergency room, chest pain units, catheterization laboratory, or otherwise were registered on a screening log, but they were not enrolled until the diagnosis of ACS was confirmed. Patients who had been in another hospital for a short (<12h) observation period and were transferred for diagnosis and management were also registered, and information from the referring hospital was sought. However, patients who were referred only for a specific treatment (i.e., cardiac catheterisation or coronary bypass surgery) were not included. The full case report form was filled out for patients with a discharge diagnosis of unstable angina or AMI. We recorded the discharge diagnosis made by the attending physicians based on the following categories: unstable angina, non-Q-wave AMI, and Q-wave AMI. Our analysis is based on the diagnosis made by the attending physicians, which at times may have been inaccurate. Indeed, this is the focus of the current analysis.

For all patients, the data collection officer was requested to record the qualifying values for cardiac troponin T, cardiac troponin I, CK-MB mass, CK-MB%, and CK, with the corresponding value for the upper limit of normal in the individual hospital. In addition, if subsequent values were significantly different from the qualifying value, the data collection officer was requested to enter the subsequent values. For patients who underwent a qualitative evaluation of cardiac troponin levels, we only recorded whether the patient did or did not have elevated levels, without a specific value.

In order to examine the extent of the troponin assay in our cohort, we examined the proportionof patients who had at least one examination of cardiac troponin levels reported at any time point.

In order to evaluate the correlation between biomarker levels and the diagnosis of MI, we included all patients who had at least one recorded value of any biomarker. For patients who had more than one creatine kinase assay, we ranked the biomarkers in the following hierarchy of priority, reflecting the descending degree of specificity of the assays: CK-MB mass, CK-MB%, or CK. For each patient we took the creatine kinase biomarker with the highest ranking of priority and calculated the ratio of its highest measured value to the upper limit of normal in the individual hospital. Thus, each patient was assigned a value for the ratio of the highest measured value of the most specific assay reported to the upper limit of normal of the assay in the individual hospital.

We examined the proportion of patients with elevated troponin levels who received a diagnosis of unstable angina, as well as the proportion of patients with normal troponin levels who received a diagnosis of Q-wave or non-Q-wave AMI.

Using different cutoff limits for the ratio the highest measured value of the creatine kinase assay chosen to the upper limit of normal of the chosen assay, ranging from >X1 upper limit of normal to >X10 upper limit of normal, we examined the proportion of patients with elevated creatine kinase biomarker levels who received a diagnosis of unstable angina, as well as the proportion of patients with normal biomarker levels who received a diagnosis of AMI.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Of the 10484 patients enrolled in the Euro Heart Survey ACS, 946 patients (9.0%) either did not undergo an evaluation of cardiac biomarkers or had no record of the biomarker value in the case report form. Of the 9538 patients with available biomarker values, 6036 (63.3%) had at least one troponin level recorded, 8871 (93.0%) had at least one creatine kinase level recorded (CK, CK-MB% or CK-MB mass), and 5369 (56.3%) had at least one level of troponin and creatine kinase recorded. The cardiac troponin levels were elevated in 3605 patients (37.8%), and the creatine kinase levels were above the upper limit of normal in 4796 patients (50.3%).

Of the 5369 patients with available troponin and creatine kinase levels, 2226 patients (41.5%) had elevated levels of both markers (for creatine kinase, any level above the upper limit of normal), and 1422 patients (26.5%) had normal levels of both markers. Elevated troponin levels (i.e., with normal creatine kinase levels) alone occurred in 971 patients (18.1%), and elevated creatine kinase levels alone occurred in 750 patients (14.0%).

Of the 6036 patients with available troponin values, elevated troponin levels were recorded in 648 of 2307 (28.1%) patients with a discharge diagnosis of unstable angina and in 2957 of 3729 (79.3%) patients with a discharge diagnosis of AMI (Table 1).


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Table 1 The discharge diagnosis and troponin status

 
Of the 8871 patients with available creatine kinase values (CK, CK-MB% or CK-MB mass), elevated creatine kinase levels were recorded in 848 of 3625 (23.4%) patients with a discharge diagnosis of unstable angina and in 3948 of 5246 (75.3%) patients with a discharge diagnosis of AMI (Table 2).


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Table 2 The discharge diagnosis and creatine kinase status

 
Using different cutoff limits for the ratio of creatine kinase, ranging from >X1 upper limit of normal to >X10 upper limit of normal, we found that with higher ratios, the proportion of patients given a diagnosis of unstable angina was increasingly small (Table 3).


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Table 3 The discharge diagnosis and creatine kinase status, based on the ratio of the measured creatine kinase value to the upper limit of normal value

 
Although based on the redefinition of AMI, any rise in cardiac biomarkers after coronary interventions is considered an AMI,1we performed an additional analysis excluding patients who underwent percutaneous or surgical coronary revascularization. Of the patients who did not undergo a revascularization procedure and had available troponin values, 23.7% of those with a discharge diagnosis of unstable angina had elevated troponin levels, as compared with 77.2% and 81.2% of those with non-Q- and Q-wave AMI, respectively.

We also examined the use of troponins and the adherence to the new definition of AMI based on the academic status of the participating hospitals. Of the 6820 patients enrolled in academic hospitals, 3996 (58.6%) reported the result of at least one troponin assay, as compared with 1721 of 3022 patients (57.0%) in non-academic hospitals (p=0.13 for academic vs. non-academic hospitals). Of the 642 patients enrolled in hospitals that were not categorized based on academic status, 49.7% reported the result of a troponin assay. In academic hospitals, 23.2% and 79.8% of the patients with a discharge diagnosis of unstable angina and AMI, respectively, had elevated troponin levels. In non-academic hospitals, 36.8% and 77.2% of the patients with a discharge diagnosis of unstable angina and AMI, respectively, had elevated troponin levels (p<0.001 for comparison of discharge diagnosis of unstable angina, and p=0.08 for comparison of discharge diagnosis of AMI).

In order to determine whether the use of troponins or the adherence to the new definition of AMI changed over time, we divided the survey cohort into two groups; patients enrolled up to 31 December 2000 and those enrolled thereafter. Of the 7341 patients enrolled up to 31 December 2000, 651 patients (8.9%) either did not undergo an evaluation of cardiac biomarkers or had no record of the biomarker value in the case report form. Of the remaining 6690 patients, 4234 (63.3%) had at least one troponin level recorded. Of the patients with available troponin values, 2529 (59.7%) had at least one elevated value recorded; 468 (28.7%) of 1632 unstable angina patients and 2061 (79.2%) of 2602 AMI patients. Likewise, of the 6198 patients with available creatine kinase levels, 604 (23.6%) of the 2556 unstable angina patients and 2750 (75.5%) of 3642 AMI patients had at least one value above the upper limit of normal. Of the 3143 patients enrolled after 31 December 2000, 295 (9.4%) either did not undergo an evaluation of cardiac biomarkers or had no record of the biomarker value in the case report form. Of the remaining 2848 patients, 1802 (63.3%) had at least one troponin level recorded. Of the patients with available troponin values, 1076 (59.7%) had at least one elevated value recorded; 180 (26.7%) of 675 unstable angina patients and 896 (79.5%) of 1127 AMI patients. Likewise, of the 2673 patients with availablecreatine kinase levels, 244 (22.8%) of the 1069 unstable angina patients and 1198 (74.7%) of 1604 AMI patients had at least one value above the upper limit of normal. Thus, there was no significant difference between the two time periods.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
4.1. New definition of AMI
Although AMI has been recognized as a clinical and pathological entity for many years, the definition of AMI remains conceptually complex. A consensus document sponsored by the European Society of Cardiology and the American College of Cardiology adopted the concept that AMI is defined by any amount of myocardial necrosis caused by ischaemia.1With the advent of increasingly more sensitive biomarkers of myocardial necrosis, small amounts of myocardial necrosis may be detected and recognized as AMI. The more recent definition has shifted the focus to the sensitive biomarkers of myocardial necrosis, in particular the troponins, and reduced the relative weight of the accompanying criteria (symptoms, clinical scenarios, and electrocardiographic changes), by allowing a very broad range of interpretations for the existence of these other criteria. However, the new definition still requires two criteria: (symptoms or electrocardiographic changes as well as elevated cardiac biomarkers). In contrast, the original World Health Organization definition of AMI requires a combination of two of three characteristics: typical symptoms of cardiovascular disease, a characteristic rise and fall in cardiac enzyme levels, and a typical electrocardiographic pattern involving the development of injury current and/or Q waves.3This more conservative definition of AMI, used primarily for epidemiological studies rather than clinical practise, excludes a large number of patients, especially those with non-Q-wave AMI. Thus, it is no wonder that physicians attending to ACS patients find it difficult to adopt the new definition that gives biochemical tests equal or even greater significance than classical cardiac elements such as a thorough assessment of the patient's symptoms and in-depth scrutiny of the electrocardiogram. A similar reluctance to diagnose AMI primarily based on the levels of cardiac enzymes has also been demonstrated in randomized studies of non-ST-segment elevation-ACS.4

4.2. Main finding
The new definition of AMI1was published on 4 September 2000. Our survey2that also began on 4 September 2000 offers unique insight regarding the implementation of this new definition in clinical practice. The main findings of our current analysis from this survey are that the recommended measures generating the new criteria, namely the troponin assays, were either not available or not used in a large proportion of ACS patients. Indeed, only 63.3% of the patients in our cohort underwent an examination for troponin levels.

Moreover, our current analysis demonstrates that a substantial proportion of ACS patients with elevated levels of cardiac biomarkers were given a diagnosis of unstable angina, and patients with normal levels of biomarkers were given a diagnosis of AMI. When we used higher levels of biomarkers to define AMI, the proportion of ACS patients with values above the cutoff level given a diagnosis of AMI substantially declined. Thus, it seems that some physicians still have not adopted the concept that any amount of myocardial necrosis caused by ischaemia constitutes AMI, but rather they demand a substantial amount of myocardial necrosis caused by ischaemia to define AMI.

4.3. Clinical implications
The implementation of new guidelines heavily relies on the availability of the required means to apply the recommendations. The current guidelines that define AMI require the availability of cardiac troponin assays. Perhaps of even greater clinical significance, cardiac troponin levels have a crucial role in tailoring the management of non-ST segment elevation ACS patients, based on current guidelines.5However, for some countries and some hospitals cardiac troponin assays remain beyond reach due to cost issues. Indeed, given that our survey included a substantial proportion of academic hospitals with revascularization facilities,2the true use of cardiac troponin assays in less well-equipped hospitals may be even smaller. Our results indicate that to conform to current guidelines in this broad region of Europe and the Mediterranean basin, there is a genuine need to increase the application of troponin assays, and more so to provide the means for their application.

Physician education is another key component of guideline implementation. Our results indicate that a substantial proportion of physicians who attend to ACS patients are either unaware of or have not accepted the new definition of AMI.6Alternatively, they may also not rely on the accuracy of the biochemical assays performed in their hospitals.6–8More efforts are therefore needed to disseminate the conceptual reasoning behind the new guidelines to ensure their more widespread acceptance and to increase the technical quality of biomarker assays. Indeed, if the technical shortcomings of current assays will not be resolved, the validity of the current definition may be challenged.7,8

4.4. Limitations
The limitations of the Euro Heart Survey ACS have been previously discussed in detail.2The final diagnosis given by the attending physician may have been erroneous. We did not examine the accuracy of the diagnosis, but rather its correlation to the recorded biomarker levels. In addition, we did not record the exact timing of the test reported, precluding any analysis regarding the interaction between procedures and adverse events and the rise in cardiac biomarkers. Because the serum levels of each biomarker have unique kinetics, the recorded values may reflect tests taken either too early or too late. To partially address this concern, in the current analysis we considered an abnormally high level of a biomarker at any time point to be suitable for a diagnosis of AMI. However, given the large proportion of patients that did not undergo cardiac troponin testing in our survey and that some of the troponin tests may have been performed either too early or too late, our finding of widespread discordance between biomarker levels and the final diagnosis probably underestimates the true extent of the phenomenon.


    5. Conclusions
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Cardiac troponin assays are still not universally available for the evaluation of ACS patients. A substantial proportion of patients receive a diagnosis of unstable angina or AMI, irrespective of the result of biomarker assays, indicating that the new definition of AMI has not yet been universally adopted, and that additional physician education is warranted to ensure its appropriate implementation, concomitantly with efforts to improve the technical quality of current assays. Future surveys such as the Euro Heart Survey ACS are needed to verify the appropriate application of guidelines in ACS patients.


    Acknowledgments
 
Sponsored by Schering-Plough and Centocor


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. A consensus document — Myocardial infarction redefined. Eur Heart J. 2002;21:1502–1513.[CrossRef]
  2. Hasdai D, Behar S, Wallentin L et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and theMediterranean basin: The Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J. 2002;23:1190–1201.[Abstract/Free Full Text]
  3. Gillum RF, Fortmann SP, Prineas RJ et al. International diagnostic criteria for acute myocardial infarction and stroke. Am Heart J. 1984;108:150–158.[Medline]
  4. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Supression Using Integrilin Therapy (PURSUIT). N Engl J Med. 1998;339:436–443.[Abstract/Free Full Text]
  5. Bertrand ME, Simoons ML, Fox KAA et al. Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation. Eur Heart J. 2000;21:1406–1432.[Free Full Text]
  6. Dargie H. Myocardial infarction: redefined or reinvented? Heart. 2002;88:1–3.[Free Full Text]
  7. Jaffe AS, Ravkilde J, Roberts R et al. It's time for a change to a troponin standard. Circulation. 2000;102:1216–1220.[Free Full Text]
  8. White HD. Things ain't what they used to be: Impact of a new definition of myocardial infarction. Am Heart J. 2002;144:933–937.[CrossRef][Medline]

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