More than 750,000 people receive a diagnosis of myocardial infarction (MI) each year in the United States. This large number represents a small numerator compared to the huge denominator of the total number of people evaluated for diagnosis. A vast number of people are evaluated to detect MI because its underdiagnosis has become a significant concern for physicians. A classic study from two decades ago demonstrated that 2% of people with myocardial infarction were mistakenly discharged from the emergency department (ED), and such misdiagnosis of myocardial infarction was associated with a higher risk of all-cause mortality.
Since then, the failure to diagnose MI has been a major cause of negligence lawsuits in the United States. In response, it is now common to seek the diagnosis of MI among people presenting to the emergency department even when the symptoms or signs for diagnosis are subtle, atypical, or entirely absent. Inevitably, this practice leads to the incorrect identification of MI in individuals without the diagnosis. From this perspective, we argue that the misdiagnosis of MI is now more frequently due to the incorrect identification of the diagnosis rather than being overlooked.
Although reducing the misdiagnosis of MI has been an imperative effort, the incorrect diagnosis of MI is not benign: individuals with suspected MI are routinely prescribed medical treatments that may expose them to adverse effects. Patients incorrectly assigned a diagnosis of MI are often subjected to additional testing, including costly imaging and potentially risky invasive procedures. Other forms of healthcare utilization are also inflated by erroneous diagnoses of MI, including unnecessary consultations, prolonged stays in the emergency department, and unnecessary hospitalizations.
Beyond these concerning issues, one in five of all individuals with a diagnosis of MI experiences depression, a third face financial hardships due to medication costs, and a tenth experience adverse changes in their job situation. The diagnosis can also affect an individual’s eligibility for life insurance or the cost thereof. At the population level, the overdiagnosis of MI can also have distorting effects; a misdiagnosis of MI may lead to changes in payment for hospitalizations or the improper inclusion of data in influential quality programs linked to financial incentives.
Overdiagnosis of MI: the scope of the problem
Emerging evidence suggests that the incorrect overdiagnosis of MI is more common than underdiagnosis.
One example is reflected in the results of clinical trials; several trials with central event adjudication committees have reported between 15% and 20% fewer type 1 MI events than those reported by site investigators when applying the recommendations of the Universal Definition of Myocardial Infarction working group. These data are not exclusive to clinical trial cohorts.
In a multicenter population with clinically diagnosed MI, 9% of events were refuted and reclassified as myocardial injury when adjudicated by expert consensus. Studies incorporating cardiac magnetic resonance imaging also point to overdiagnosis. For example, in the Women’s Heart Attack Research Program, only half of patients with clinically diagnosed MI had an infarction pattern on their cardiac magnetic resonance imaging result, and alternative diagnoses such as myocarditis were identified for a fifth of participants.
However, unlike studies focused on the relatively small number of patients with undetected myocardial infarction who are discharged from the emergency department, there is little data on the frequency and consequences of incorrect overdiagnosis of myocardial infarction.
Factors contributing to the overdiagnosis of MI
The Universal Definition of Myocardial Infarction working group defines the diagnosis based on symptoms and signs of coronary ischemia along with evidence of myocardial injury reflected in an increase in cardiac troponin level, a decrease in level, or both. Although an abnormal troponin level is necessary to make a diagnosis of MI, that result alone is not sufficient to do so. Compounding this problem, liberal troponin testing has become common, particularly in the United States.
In one study, a quarter of individuals presenting to the emergency department underwent troponin testing and less than half complained of chest pain. Pre-test probability reduction diminishes the post-test validity of any result, an issue further complicated by the analytical aspects of increasingly sensitive troponin assays now widely available.
Firstly, these assays are often affected by non-coronary comorbidities. Because patients undergoing evaluations in the emergency department tend to be older and with more comorbidities, abnormalities in troponin level in the absence of MI are common; among unselected emergency department cohorts, approximately 1 in 7 patients will have an elevated concentration.
Secondly, although troponin level represents the most specific biomarker for diagnosing myocardial infarction, mechanisms beyond ischemic necrosis, such as apoptosis and exocytosis (which can occur in non-coronary pathological states), are involved in troponin elevation. Therefore, abnormal troponin concentrations, even when dynamic, do not necessarily reflect ischemic necrosis of the myocardium.
Thirdly, although the upper reference limit of the 99th percentile for high-sensitivity troponin (derived from apparently healthy adult cohorts) is fundamental for diagnosing MI, this value is generally derived from cohorts of young or middle-aged adults (<59 years); if identified among older adults (≥60 years), the 99th percentile for that age category would be 1.5 to 2.0 times higher. Because most MIs occur in older individuals, these data raise the possibility of overdiagnosis of MI in older adults if troponin thresholds derived from generally younger and healthier individuals are used.
Fourthly, although the 99th percentile value represents an accepted criterion for diagnosing myocardial injury, there is a complete lack of understanding about the optimal values to identify abnormal troponin level increase or decrease associated with MI. For all these reasons, in the context of frequent testing with low pre-test probability and analytical vulnerabilities of troponin tests upon which much reliance is placed for the diagnosis of MI, the positive predictive value of a troponin test result for MI in the United States is significantly lower (≈16%) than in the United Kingdom (≈60%). This lower positive predictive value of troponin test result for myocardial infarction in studies conducted in the United States strongly supports that excessive testing and misdiagnosis are occurring.
Strategies to reduce overdiagnosis of MI
There are several opportunities to reduce the risk of overdiagnosis of myocardial infarction. While overlooking a diagnosis of MI should never occur, damage reform laws are needed to limit payments for non-economic damages in cases of negligence to curb defensive medicine practices; such laws can reduce healthcare costs without sacrificing quality of care.
Beyond this step, pre-test probability should be considered before troponin testing; such tests should be applied only to individuals with suspected acute coronary syndrome and not applied relatively non-selectively to individuals presenting to the emergency department.
Machine learning models have the potential to improve the accuracy of diagnosing MI beyond current MI diagnostic pathways. Such models can incorporate fixed and dynamic variables to more accurately predict the diagnosis of MI. Implementing age-specific 99th percentiles to reduce overdiagnosis of abnormal troponin concentrations in older adults should be considered.
Moreover, it is vitally important to improve compliance with guidelines on the Universal Definition of Myocardial Infarction, paying attention to definition aspects that are not biomarkers; relying solely on troponin level to make a diagnosis of MI carries risks of misdiagnosis. Beyond troponin, specific biomarkers for detecting myocardial necrosis as opposed to myocardial injury need to continue to be
developed. Finally, the judicious use of cardiac imaging, particularly in ambiguous cases, can provide an additional opportunity to improve the accuracy of diagnosing MI.
Conclusions
Overdiagnosis, unlike underdiagnosis, may now be the dominant form of misdiagnosis of MI. Overdiagnosis of MI is not benign and exposes patients to risks of unnecessary testing, treatments, and costs and can distort both hospital payments and the intended effects of health policies. Further studies are needed to better understand the frequency and implications of overdiagnosis of MI while identifying, evaluating, and implementing strategies to ensure appropriate and accurate evaluations for diagnosis.
