EDITORIAL COMMENT
Continuous ST-Segment Monitoring in Contemporary Acute Coronary Syndrome PatientsThe Magic of MERLIN–TIMI 36*
Dan Tzivoni, MD ,* and
Mitchell W. Krucoff, MD
Cardiology Department, Shaare Zedek Medical Center, Jerusalem, Israel
Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina
* Reprint requests and correspondence: Dr. Dan Tzivoni, Director, Cardiology Department, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel (Email: tzivoni{at}szmc.org.il).
Key Words: acute coronary syndrome • electrocardiography • Holter • ranolazine
Acute coronary syndrome (ACS) is characterized by repeated transient ischemic episodes (TIE), which can be symptomatic or silent. The frequency of TIE reported in patients with ACS varies from 15% to 77% across studies, due to variations in inclusion/exclusion criteria, modalities of therapy, monitoring period and number of leads used for continuous electrocardiographic (cECG) monitoring (1,2). Klootwijk et al. (2) detected ischemic changes in 77% of 130 patients with unstable angina pectoris (UAP) using 12-lead cECG monitoring for 48 h. In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) study (3), monitoring 220 patients with non–ST-segment elevation (NSTE) ACS for 48 h with 3-lead Holter, Goodman et al. (3) recorded TIE in 25%. Akkerhuis et al. (4), who obtained data from the CAPTURE (C7E3 Fab Anti Platelet Therapy in Unstable Refractory Angina), the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy), and the FROST (French Randomized Optimal Stenting Trial) studies in patients with NSTE ACS found ischemic episodes in 27% of 995 patients who had 24-h cECG monitoring. Langer et al. (5) reported ischemic changes in 66% of 135 patients with UAP.
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Mechanism
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Ischemia on cECG has been described in association with both severe and high risk morphology coronary anatomy in ACS patients. Bugiardini et al. (6) described prolonged (>60 min) duration of myocardial ischemia on Holter monitoring of patients with complex coronary disease, and Pozzati et al. (7) reported both prolonged duration (85 vs. 33 min) and more frequent TIE (56% vs. 9%) in such patients compared to patients with smooth, less complex lesions. Like Scirica et al. (8) and the TIMI 36 (Thrombolysis In Myocardial Infarction 36) group, who in this issue of the Journal report an increased incidence of ischemia in patients with greater extent of coronary disease (12.3% of patients with single-vessel disease, 18.9% with double-vessel disease, and 28.0% with triple-vessel disease), Patel et al. (9) found that the dichotomous presence or absence of TIE was a very powerful predictor of complex coronary lesion or coronary thrombus (odds ratio: 7.1), whereas Langer et al. (5) reported more left main and severe multivessel disease in patients with TIE.
Patients with ACS have impaired endothelial function with increased tendency for coronary vasoconstriction (10,11). Scirica et al. (8) document ST-segment shifts in >10% of patients without flow-limiting coronary lesions, as well as in patients after complete revascularization with percutaneous coronary intervention. The combination of more complex and more advanced coronary pathology as well as increased coronary tone may provide further mechanistic insight into how strongly TIE relate to impaired prognosis even in the most modern setting of medical and percutaneous coronary intervention therapy.
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Prognosis
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Studies involving patients with NSTE ACS have consistently demonstrated that the presence of TIE is predictive of both short and long-term increase in mortality and infarction. Gottlieb et al. (12) were the first to demonstrate that TIE (mostly silent), which were present in 37 of 70 patients with UAP under best medical treatment, were the best predictors of early cardiac events among 15 tested variables. Similarly, in the 135 patients with UAP mentioned above, Langer et al. (5) found a higher frequency of cardiac events (48% vs. 20%) among patients with TIE than among patients without TIE. In the meta-analysis from the CAPTURE, PURSUIT, and FROST studies, Akkerhuis et al. (4) found death and myocardial infarct in 5.7% of patients without ischemic episodes, compared with 19.7% of patients who had  5 episodes. In the ESSENCE trial, Goodman et al. (3) reported death or myocardial infarction at 1 year in 18.4% of patients with TIE and in 8.3% of patients without TIE. Yan et al. (13) investigated the additional prognostic information of 48-h cECG monitoring in 681 NSTE ACS patients. Over 30 months, patients with ST-segment shifts had a higher risk of death (17.7% vs. 5.9%) or death and myocardial infarction (24.6% vs. 11.1%). In multivariate analysis adjusting for the GRACE (Global Registry of Acute Coronary Events) risk score, the presence of ST-segment shifts remained an independent predictor of death (hazard ratio: 2.37, p = 0.002) and death/myocardial infarction (hazard ratio: 1.93, p = 0.003).
Scirica et al. (8) report their experience from the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36) trial of 6,355 patients undergoing an average of 6 days of uninterrupted 2-lead Holter monitoring of patients presenting with ACS randomly assigned to treatment with Ranolazine or placebo, stratified by conservative versus early invasive strategies. In this landmark study, the authors confirm that despite all modern advances in therapy, 20% of patients have TIE, and these patients have higher mortality and morbidity than do patients without TIE. The TIE were more commonly present in patients with a high-risk profile, namely, older patients (age >65 years) with impaired renal function, prior angina or heart failure, and ischemic changes on ECG at presentation. The TIE also predicted added risk beyond models using several clinical and laboratory parameters. In patients with TIE, the adjusted hazard ratio for cardiovascular death was 2.46 (p < 0.001). The hazard ratio for cardiovascular death with TIE was higher for every subgroup of patients: 2.7 for patients >65 years of age and 2.3 for patients <65 years of age, 2.8 for prior angina, 3.2 for previous myocardial infarction, 2.8 for previous heart failure, 2.6 for TIMI risk score of 5 to 7, 3.0 for treatment with conservative strategies and 2.2 for treatment with early invasive strategy, 3.8 for ejection fraction 40%, 3.0 for positive troponin and 4.7 for negative troponin, and 4.7 for normal levels of brain natriuretic peptide and 2.3 for elevated levels. Even in a very low clinical risk population (negative troponin, low level of brain natriuretic peptide, no ECG changes on admission) or ejection fraction 40%, the presence of TIE was associated with significantly elevated hazard ratio for death of 2.2 to 4.3, compared with similar patients who had no TIE.
The presence or absence of symptoms during TIE is not reported for the MERLIN–TIMI 36 cohort. That represents a limitation to understanding the potential prognostic differences between silent and symptomatic TIE, with the possibility to further risk stratify this patient group.
Unlike many previous studies, continuous variables, such as the frequency and duration of ischemia, did not carry prognostic information in the MERLIN–TIMI 36 trial experience beyond the dichotomous presence or absence of TIE per se, although there were some suggestive numerical trends. Furthermore, by performing 6 days of cECG monitoring, the authors were able to demonstrate that late ischemic episodes (beyond 72 h) were detected in only 5% of patients managed with a conservative strategy, and in only 2.5% of patients managed with an aggressive strategy.
The use of cECG acutely for 24 to 72 h using 12-lead Holter monitoring, followed by exercise testing 5 to 7 days later, was not tested in the MERLIN–TIMI 36 trial as an alternative to a week of 2-lead Holter monitoring. That might yield more predictive information, as discussed below, with less logistical burden. It is widely appreciated that almost all patients who have TIE during ambulatory monitoring have abnormal exercise tests (14), and by 5 to 7 days, most ACS patients are ambulatory and can safely perform exercise tests.
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Technical Aspects of ST-Segment Monitoring for TIE
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Signal fidelity, number of leads, lead location, and duration of monitoring are all key aspects of TIE quantification. Scirica et al. (8) used 2 bipolar leads at a 128-Hz sampling rate, whereas in other reports, continuous 3-lead vectorcardiographs or 12-lead cECG sampling at 500 to 1,000 Hz was used. This is an important difference because not only is ischemia episodic in time, but also it is focal over the precordial "space" as well (15). Too few precordial leads may miss TIE altogether or may underestimate duration or peak ST-segment deviation of TIE (2,16), a potential factor in why number of episodes, ischemia duration, and ST-segment deviation curve area were not predictive of clinical outcomes in the MERLIN–TIMI 36 report.
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Conclusions
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This study by Scirica et al. (8) is the largest and most contemporary report of continuous Holter ST-segment monitoring of patients with coronary artery disease in the literature, and thus provides unique statistical power to examine key subgroups of interest. This study strongly confirms that TIE and/or ST-segment shift have prognostic significance for ACS patients, patients treated medically and/or undergoing percutaneous coronary intervention, patients with both complete and incomplete revascularization, and patients who are otherwise categorized as high or low risk using contemporary serologic markers and descriptor models.
Despite the very clear prognostic value of the information obtained from cECG monitoring and guidelines supporting this concept, at present it is not yet practical to perform continuous monitoring of all ACS patients for clinical purposes, as accurate and reliable online automated ischemia detection systems are not available. Even if and when such systems are developed, to go beyond research applications, it will be critical to show that cECG-guided therapy actually can lead to improved outcomes.
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Footnotes
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Dr. Krucoff has received research grants and consulting fees from Philips Medical, GE Medical, Mortara Instrument, Heartscope, NorthEast Monitoring, and NewCardio.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Jernberg T, Lindahl B, Wallentin L. Continuous multilead ST-segment monitoring should be a part of the clinical routine Eur Heart J 2002;23:918-921.[Free Full Text]2. Klootwijk P, Meij S, Es GAv, et al. Comparison of usefulness of computer assisted continuous 48-h 3-lead with 12-lead ECG ischaemia monitoring for detection and quantitation of ischaemia in patients with unstable angina Eur Heart J 1997;18:931-940.[Abstract/Free Full Text] 3. Goodman SG, Barr A, Sobtchouk A, et al. ESSENCE Substudy Group Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q wave myocardial infarction: the Canadian ESSENCE ST-segment monitoring substudy J Am Coll Cardiol 2000;36:1507-1513.[Abstract/Free Full Text] 4. Akkerhuis KM, Klootwijk PAJ, Lindeboom W, et al. Recurrent ischaemia during continuous multilead ST-segment monitoring identifies patients with acute coronary syndromes at high risk of adverse cardiac events Eur Heart J 2001;22:1997-2006.[Abstract/Free Full Text] 5. Langer A, Freeman MR, Armstrong PW. ST-segment shift in unstable angina: pathophysiology and association with coronary anatomy and hospital outcome J Am Coll Cardiol 1989;13:1495-1502.[Abstract] 6. Bugiardini R, Pozzati A, Borghi A, et al. Angiographic morphology in unstable angina and its relation to transient myocardial ischemia and hospital outcome. Am J Cardiol 191;67:460–4. 7. Pozzati A, Bugiardini R, Borghi A, et al. Transient ischaemia refractory to conventional medical treatment in unstable angina: angiographic correlates and prognostic implications Eur Heart J 1992;13:360-365.[Abstract/Free Full Text] 8. Scirica BM, Morrow DA, Budaj A, et al. Ischemia detected on continuous electrocardiography after acute coronary syndrome: observations from the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36) trial J Am Coll Cardiol 2009;53:1411-1421.[Abstract/Free Full Text] 9. Patel DJ, Gomma AH, Knight CJ, et al. Why is recurrent myocardial ischaemia a predictor of adverse outcome in unstable ischemia? Eur Heart J 2001;22:1991-1996.[Abstract/Free Full Text] 10. Lerman A, Zeiher AM. Endothelial function, cardiac events Circulation 2005;111:363-368.[Free Full Text] 11. Fichtlscherer S, Breuer S, Zeiher AM. Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the "vulnerable" patient Circulation 2004;110:926-932. 12. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina N Engl J Med 1986;314:1214-1219.[Web of Science][Medline] 13. Yan AT, Yan RT, Tan M, et al. INTERACT Investigators Long-term prognostic value and therapeutic implications of continuous ST-segment monitoring in acute coronary syndrome Am Heart J 2007;153:500-506.[CrossRef][Web of Science][Medline] 14. Tzivoni D, Gavish A, Benhorin J, Keren A, Stern S. Myocardial ischemia during daily activities and stress Am J Cardiol 1986;58:478-508. 15. Fox KM, Deanfield J, Ribero P, England D, Wright C. Projection of ST segment changes on to the front of the chest. Practical implications for exercise testing and ambulatory monitoring. Heart 1982;48:555-559.[Free Full Text] 16. Krucoff MW. Poor performance of lead V5 in single and dual channel ST-segment monitoring during coronary occlusion J Electrocardiol 1988;21:S30-S34.[CrossRef][Web of Science][Medline]
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