Author + information
- Bruce R. Brodie, MD∗ ()
- LeBauer Cardiovascular Research Foundation, Cone Health Heart and Vascular Center, Greensboro, North Carolina
- ↵∗Reprint requests and correspondence:
Dr. Bruce R. Brodie, Cone Health Heart and Vascular Center, LeBauer Cardiovascular Research Foundation, 313 Meadowbrook Terrace, Greensboro, North Carolina 27408.
Men talk of killing time, while time quietly kills them.
—Dion Boucicault, 19th-century Irish-American playwright (1)
Reperfusion therapy, first with fibrinolytics and now with primary percutaneous coronary intervention (PCI), has revolutionized the management of patients with ST-segment elevation myocardial infarction (STEMI). Over the past 25 years, short-term mortality in STEMI patients has fallen from 13% in the control arms of early fibrinolytic trials in the 1980s to 2% to 4% in contemporary trials in patients treated with primary PCI and optimal adjunctive therapies.
It was recognized very early that time to treatment is a crucial metric in determining outcomes with reperfusion therapy. Early fibrinolytic trials and more recent primary PCI trials have documented that delays in reperfusion resulting in prolonged ischemic time have translated into increased mortality (2,3). Eitel et al. (4) have graphically shown that myocardial salvage by magnetic resonance imaging falls off rapidly with increasing time to treatment with primary PCI. Much data have been accumulated supporting the mantra that “time is muscle” and that delays in time to reperfusion are associated with increased mortality. Dion Boucicault’s quote describes the passage of time and the mortality of man, but could just as well describe the passage of time and mortality from myocardial infarction—time (not so) quietly kills.
Considering the critical importance of ischemic time as a metric in reperfusion therapy for STEMI patients, it is ironic and somewhat disturbing that the measure of ischemic time depends entirely upon the patient’s subjective determination of the time of onset of his/her symptoms. Mahmoud et al. (5) in this issue of JACC: Cardiovascular Interventions have presented an observational study that provides a more objective estimate of the time of onset of myocardial infarction that could alter our understanding of the relationship between ischemic time and outcomes with reperfusion therapy.
The Mahmoud et al. study (5) compares patient-reported symptom onset time with biological onset time determined from serial troponin levels in STEMI patients undergoing primary PCI. The authors calculated the time of initial troponin elevation by fitting a regression line to the rising troponin levels after logarithmic transformation of both time and troponin levels, and extrapolating backwards to estimate the time of initial troponin elevation (a troponin value of 0.01 ng/ml). The time of onset of myocardial infarction was set at 4 h before initial troponin elevation, on the basis of clinical and pre-clinical studies relating the time of coronary occlusion to initial troponin elevation.
The authors found that the time of onset of myocardial infarction by this method (biological onset time) was 4.2 h earlier than patient-reported symptom onset time, and these differences were more pronounced in elderly patients, patients with low body mass index, no previous PCI, initial Thrombolysis In Myocardial Infarction (TIMI) flow grade >0, and patients at higher risk of mortality. The validity of this method was supported by the observation that ischemic time based on biological onset time correlated with 1-year mortality and infarct size estimated by peak troponin levels, whereas ischemic time based on reported symptom onset time did not.
It is somewhat surprising that the differences in biological onset time and symptom onset time were so great. This may partly be related to the constant chosen (4 h) to represent the time from coronary occlusion to first troponin elevation, which is somewhat arbitrary. Determination of this constant is problematic because animal models evaluating the time from coronary occlusion to troponin elevation may not translate directly to the human situation, and evaluations comparing symptom onset time to first troponin elevation would be using measurements from a standard we are trying to replace. It is known that the process of coronary occlusion leading to STEMI is often a dynamic process with a series of small plaque ruptures with partial coronary occlusion and distal embolization of platelet aggregates and thrombus, usually leading up to complete coronary occlusion with ST-segment elevation. Sometimes, these early plaque ruptures may be silent but lead to troponin release, so it is understandable that the time of first troponin elevation sometimes occurs before the onset of symptoms, as was shown in this paper (5).
The investigators point out that patients frequently have problems reporting the onset of symptoms, and this may also contribute to the wide difference between biological onset time and symptom onset time. Elderly patients may have difficulty remembering the time of symptom onset, diabetic patients frequently have silent ischemia, and women frequently have atypical symptoms with ischemia. Patients with TIMI flow grade >0 on initial angiography are more likely to have a series of plaque ruptures without complete occlusion with stuttering symptoms or no symptoms, and this may explain the greater difference between biological onset time and symptom onset time in this group of patients.
The study has some important limitations. Many STEMI patients treated with primary PCI were excluded from the study because there were no data on patient-reported symptom onset time or because serial troponin values were not available. Only 602 of 2,646 STEMI patients treated with primary PCI during the study period were included, and compared with excluded patients, this was a low-risk group with hospital and 1-year mortality rates of only 1.8% and 5.7%, respectively. Peak troponin levels were low (median 3.7 ng/ml), probably because troponin levels were not routinely collected beyond 6 h, and this could potentially affect the assessment of infarct size and the relationships between ischemic time and infarct size. Finally, as the authors point out, because reperfusion with primary PCI can affect troponin levels because of washout, these data cannot be applied to STEMI patients who do not receive reperfusion therapy or who are treated with fibrinolytic therapy.
A major limitation of biological onset time, as determined in this study (5), is that it cannot be used prospectively, because 2 elevated troponin values are needed to make the assessment. The method may still be used in retrospective analyses of clinical trials to better understand the relationship between ischemic time and outcomes with various reperfusion strategies and with new adjunctive therapies. Perhaps even more exciting are the possibilities that new technology could allow prospective assessment of biological onset time. The use of multiple markers of myocardial injury with varied release kinetics measured at the time of patient presentation could potentially allow an estimate of the time of onset of myocardial infarction. For example, high-sensitivity cardiac troponin measurements can be detected sooner after the onset of symptoms than standard cardiac troponin measurements, and these could be used to help stratify the time of onset of myocardial infarction (6).
If the results of this study are confirmed by larger trials, and if methodology can be developed to allow prospective estimates of ischemic time, the new methodology could potentially impact clinical practice. Ischemic time is critical early after the onset of myocardial infarction, and delays to reperfusion during this early time period have a major adverse effect on outcomes, whereas delays later after the onset of myocardial infarction are less critical (7). A more objective measure of ischemic time could alter strategies regarding choice of reperfusion therapy and systems of care to reduce ischemic time. Ischemic time may be critical in determining whether adjunctive therapies with primary PCI will be effective. Therapies aimed at reducing infarct size, such as cooling, distal protection against embolization, and pharmacological agents, have the potential to be beneficial early after the onset of myocardial infarction, when myocardial salvage is possible, but not later. A better method of assessing ischemic time might allow targeting patients more likely to benefit from such therapies.
The Mahmoud et al. study (5) offers a new method and exciting possibilities for re-assessing the relationship between ischemic time and outcomes in STEMI patients treated with primary PCI and adjunctive therapies. New studies with this or similar methodologies could alter current paradigms and impact clinical practice. We may see a new time clock for STEMI.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Brodie has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2015 American College of Cardiology Foundation
- ↵Boucicault, Dion. London Assurance. Rev. ed. London: Oberon Books, 2013.
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