STEMI onset typically precedes patient-reported symptoms, and the total ischemic time—from first troponin release to reperfusion—outperforms symptom-based ischemic time in predicting 1-year mortality, according to a study published in the May 2015 issue of JACC: Cardiovascular Interventions. In addition, underestimation of actual ischemic time is more pronounced in high-risk patients.   

“Further prospective validation of our findings is warranted,” write David R. Holmes Jr, MD, of The  the Mayo Clinic (Rochester, MN), and colleagues. “In the meantime, clinicians should be aware of this phenomenon and also take into account other factors that reflect ischemic time, such as Q waves on the baseline electrocardiogram.”

The investigators analyzed data on 607 STEMI patients (mean age 62.6 years; 23% women) who underwent primary PCI at the Mayo Clinic between 2004 and 2012 and were enrolled in its PCI registry.

On angiography, TIMI flow grade 0 was found in 62% of patients and multivessel disease in 65%. The average number of troponin T measurements was 3.2, with 2.7 of those, on average, showing increased levels. Biochemical onset time was calculated by backward extrapolation from serial increasing troponin T measurements, which were obtained on admission and at 3 and 6 hours via immunoassay (Elecsys, Roche Diagnostics). Biochemical ischemic time was defined as the period from biochemical onset to treatment, whereas conventional ischemic time was the time from reported symptom onset to treatment.

The median symptom onset time was 12 minutes later than the estimated time of first troponin increase. Assuming an interval of 4 hours from coronary occlusion to first troponin increase, biochemical onset time tended to be earlier than reported symptom onset, with a median difference of -4.2 hours (P < .001).

Compared with the reference population, biochemical onset was earlier among patients with:

• Preprocedural TIMI flow grade greater than 0  
• Age at least 65 years  
• BMI < 28 kg/m²  
• No prior PCI

There were no differences in subgroups based on sex, diabetes, or night onset of symptoms.

Biochemical Ischemic Time More Closely Tied to Mortality

When calculated using reported symptom onset time, median ischemic time was 3.7 hours. When recalculated using biochemical onset time, median ischemic time was 8.6 hours. Overall, biochemical ischemic time tended to be longer than conventional ischemic time, but the 2 measures showed good agreement in patients with ischemic times longer than 12 hours (P < .001 for overall correlation).

The median peak troponin level was 3.7 ng/mL. Although conventional ischemic time did not correlate with peak troponin (P = .61)—a surrogate for infarct size—there was a positive correlation between biochemical ischemic time and peak troponin (P = .001).

At follow-up, in-hospital and 1-year mortality were 1.8% and 5.7%, respectively. While no association was seen between conventional ischemic time and 1-year mortality, biochemical ischemic time predicted that outcome (HR 1.70 per doubling; 95% CI 1.20-2.40). Furthermore, a higher ratio of biochemical to conventional ischemic time predicted increased 1-year mortality (HR 1.60 per doubling; 95% CI 1.18-2.18), which the authors say indicates that shorter symptom-based ischemic time relative to biochemical ischemic time was more common in patients at higher risk.

Adjustment of the constant factor between coronary occlusion and initial troponin increase to 2 hours reduced the median difference between chemical onset time and symptom onset time to -2.2 hours but did not substantially affect any of the other analyses. Results were also similar after exclusion of patients with postprocedural TIMI flow grade less than 3. According to the authors, this argues against bias in the modeling process due to troponin washout after reperfusion.

Calculation of Biochemical Onset Includes Arbitrary Element

“Use of biochemical onset time in future studies may enhance our knowledge about the interaction between time from symptom onset, reperfusion strategy selection, and outcome in STEMI patients,” the authors suggest.

Nonetheless, they caution, when assessing this method it is important to understand how biochemical onset time was derived. In particular, because the 4 hours subtracted from the point of initial troponin release—to account for the time required to reach the peripheral circulation—is somewhat arbitrary, the difference between biochemical onset time and symptom onset time “should be interpreted with caution,” they acknowledge.

Dr. Holmes and colleagues offer possible explanations for exacerbated discrepancies between symptom and biochemical onset times seen in certain subgroups. For example, they suggest:

• Elderly patients more often present with dyspnea and faintness, which initially may not be recognized as cardiac symptoms; also, older patients may be less accurate in recalling onset time.
• Patients with a TIMI flow grade greater than 0 on angiography may have had a “stuttering MI” with waxing and waning symptoms.
• Nonobese patients and those with no prior PCI may not have been made aware of MI symptoms by their physicians.

‘A New Time Clock for STEMI’?

“Considering the critical importance of ischemic time as a metric in reperfusion therapy for STEMI, 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,” writes Bruce R. Brodie, MD, of the Cone Health Heart and Vascular Center (Greensboro, NC), in an accompanying editorial. However, the researchers’ more objective method of estimating the time of STEMI onset could “alter our understanding of the relationship between ischemic time and outcomes with reperfusion therapy.”

A major limitation of the current approach is that it relies on serial troponin measurements and thus cannot be used prospectively, Dr. Brodie points out. Nonetheless, it “may still be used in retrospective analyses of clinical trials,” he observes.

Dr. Brodie also offers a vision of a future in which multiple biomarkers of myocardial injury with different release kinetics measured at patient presentation might allow estimation of the time of MI onset. If further studies validate the current approach, such technology “could alter strategies regarding choice of reperfusion therapy and systems of care to reduce ischemic time,” he suggests. Measures such as cooling, distal protection against embolization, and pharmacological agents “have the potential to be beneficial early after the onset of [MI], when myocardial salvage is possible,” he continues. In addition, “a better method of assessing ischemic time might allow targeting of patients who are more likely to benefit from such therapies.

“New studies with this or similar methodologies could alter current paradigms and impact clinical practice,” Dr. Brodie concludes. “We may see a new time clock for STEMI.”

Sources: 
1. Mahmoud KD, Hillege HL, Jaffe AS, et al. Biochemical validation of patient-reported symptom onset time in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol Intv. 2015;8:778-787.
2. Brodie BR. A new time clock for ST-segment elevation myocardial infarction [editorial]. J Am Coll Cardiol Intv. 2015;8:788-790.

Disclosures:

• Drs. Holmes and Brodie report no relevant conflicts of interest.

Related Stories:

• Study Highlights Discrepancies in STEMI Recognition, Care Between Young Men, Women
• Female STEMI Patients Have Longer Prehospital Delays, Poorer Outcomes
• Timing of STEMI Symptoms Does Not Affect In-Hospital Mortality