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Application of MI in Clinical Trials and Quality Assurance Programs

In clinical trials, MI may be an entry criterion or an end-point. A universal definition for MI is of great benefit for clinical studies, since it will allow a standardized approach for interpretation and comparison across different trials. The definition of MI as an entry criterion, e.g. MI type 1 and not MI type 2, will determine patient characteristics in the trial. Occasionally MI occurs and, at angiography, restenosis is the only angiographic explanation.^[99,100] This PCI-related MI type might be designated as an ‘MI type 4c’, defined as ≥50% stenosis at coronary angiography or a complex lesion associated with a rise and/or fall of cTn values >99th percentile URL and no other significant obstructive CAD of greater severity following: (i) initially successful stent deployment or (ii) dilatation of a coronary artery stenosis with balloon angioplasty (<50%).

In recent investigations, different MI definitions have been employed as trial outcomes, thereby hampering comparison and generalization between these trials. Consistency among investigators and regulatory authorities, with regard to the definition of MI used as an endpoint in clinical investigations, is of substantial value. Adaptation of the definition to an individual clinical study may be appropriate in some circumstances and should have a well-articulated rationale. No matter what, investigators should ensure that a trial provides comprehensive data for the various types of MI and includes the 99th percentile URL decision limits of cTn or other biomarkers employed. Multiples of the 99th percentiles URL may be indicated as shown in (). This will facilitate comparison of trials and meta-analyses.

Table 6.  Tabulation in Clinical Trials of MI Types According to Multiples of the 99th Percentile Upper Reference Limit of the Applied Cardiac Biomarker

Because different assays may be used, including newer, higher-sensitivity cTn assays in large multicenter clinical trials, it is advisable to consistently apply the 99th percentile URL. This will not totally harmonize troponin values across different assays, but will improve the consistency of the results. In patients undergoing cardiac procedures, the incidence of MI may be used as a measure of quality, provided that a consistent definition is applied by all centers participating in the quality assurance program. To be effective and to avoid bias, this type of assessment will need to develop a paradigm to harmonize the different cTn assay results across sites.

Public Policy Implications of the Adjustment of the MI Definition

Revision of the definition of MI has a number of implications for individuals as well as for society at large. A tentative or final diagnosis is the basis for advice about further diagnostic testing, lifestyle changes, treatment and prognosis for the patient. The aggregate of patients with a particular diagnosis is the basis for health care planning and policy and resource allocation.

One of the goals of good clinical practice is to reach a definitive and specific diagnosis, which is supported by current scientific knowledge. The approach to the definition of MI outlined in this document meets this goal. In general, the conceptual meaning of the term ‘myocardial infarction’ has not changed, although new, sensitive diagnostic methods have been developed to diagnose this entity. Thus, the diagnosis of acute MI is a clinical diagnosis based on patient symptoms, ECG changes, and highly sensitive biochemical markers, as well as information gleaned from various imaging techniques. It is important to characterize the type of MI as well as the extent of the infarct, residual LV function, and the severity of CAD and other risk factors, rather than merely making a diagnosis of MI. The information conveyed about the patient’s prognosis and ability to work requires more than just the mere statement that the patient has suffered an MI. The many additional factors just mentioned are also required so that appropriate social, family, and employment decisions can be made. A number of risk scores have been developed to predict the prognosis after MI. The classification of the various other prognostic entities associated with MI should lead to a reconsideration of the clinical coding entities currently employed for patients with the myriad conditions that can lead to myocardial necrosis, with consequent elevation of biomarker values.

It should be appreciated that the current modification of the definition of MI may be associated with consequences for the patients and their families in respect of psychological status, life insurance, professional career, as well as driving- and pilots’ licenses. The diagnosis is associated also with societal implications as to diagnosis-related coding, hospital reimbursement, public health statistics, sick leave, and disability attestation. In order to meet this challenge, physicians must be adequately informed of the altered diagnostic criteria. Educational materials will need to be created and treatment guidelines must be appropriately adapted. Professional societies and healthcare planners should take steps to facilitate the rapid dissemination of the revised definition to physicians, other health care professionals, administrators, and the general public.

Global Perspectives of the Definition of Myocardial Infarction

Cardiovascular disease is a global health problem. Understanding the burden and effects of CAD in populations is of critical importance. Changing clinical definitions, criteria and biomarkers add challenges to our understanding and ability to improve the health of the public. The definition of MI for clinicians has important and immediate therapeutic implications. For epidemiologists, the data are usually retrospective, so consistent case definitions are critical for comparisons and trend analysis. The standards described in this report are suitable for epidemiology studies. However, to analyze trends over time, it is important to have consistent definitions and to quantify adjustments when biomarkers or other diagnostic criteria change.^[101] For example, the advent of cTn dramatically increased the number of diagnosable MIs for epidemiologists.^[3,102]

In countries with limited economic resources, cardiac biomarkers and imaging techniques may not be available except in a few centers, and even the option of ECG recordings may be lacking. In these surroundings, the WHO states that biomarker tests or other high-cost diagnostic testing are unfit for use as compulsory diagnostic criteria.^[3] The WHO recommends the use of the ESC/ACCF/AHA/WHF Universal MI Definition in settings without resource constraints, but recommends more flexible standards in resource-constrained locations.^[3]

Cultural, financial, structural and organizational problems in the different countries of the world in the diagnosis and therapy of acute MI will require ongoing investigation. It is essential that the gap between therapeutic and diagnostic advances be addressed in this expanding area of cardiovascular disease.

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Abbreviations and acronyms
ACCF, American College of Cardiology Foundation; ACS, acute coronary syndrome; AHA, American Heart Association; CAD, coronary artery disease; CABG, coronary artery bypass grafting; CKMB, creatine kinase MB isoform; cTn, cardiac troponin; CT, computed tomography; CV, coefficient of variation; ECG, electrocardiogram; ESC, European Society of Cardiology; FDG, fluorodeoxyglucose; h, hour(s); HF, heart failure; LBBB, left bundle branch block; LV, left ventricle; LVH, left ventricular hypertrophy; MI, myocardial infarction; mlBG, meta-iodo-benzylguanidine; min, minute(s); MONICA, Multinational MONItoring of trends and; determinants in CArdiovascular disease; MPS, myocardial perfusion scintigraphy; MRI, magnetic resonance imaging; mV, millivolt(s); ng/L, nanogram(s) per liter; Non-Q Ml, non-Q wave myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PET, positron emission tomography; pg/mL, pictogram(s) per milliliter; Q wave Ml, Q wave myocardial infarction; RBBB, right bundle branch block; sec, second(s); SPECT, single photon emission computed tomography; STEMI, ST elevation myocardial infarction; ST-T, ST-segment -T wave; URL, upper reference limit; WHF, World Heart Federation; WHO, World Health Organization;

Acknowledgments
We are very grateful to the dedicated staff of the Practice Guidelines Department of the ESC.

J Am Coll Cardiol. 2012;60(16):1581-1598. © 2012  Elsevier Science, Inc.