CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Ischemia Detected on Continuous Electrocardiography After Acute Coronary SyndromeObservations 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
Benjamin M. Scirica, MD, MPH*, ,*,
David A. Morrow, MD, MPH*,,
Andrzej Budaj, MD, PhD ,
Anthony J. Dalby, MD ,
Satishkumar Mohanavelu, MS*,
Jie Qin, MS*,
Julian Aroesty, MD*,
Chester M. Hedgepeth, MD, PhD,
Peter H. Stone, MD and
Eugene Braunwald, MD*,
* TIMI Study Group, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland
Milpark Hospital, Johannesburg, South Africa
Manuscript received October 15, 2008;
revised manuscript received December 19, 2008,
accepted December 22, 2008.
* Reprint requests and correspondence: Dr. Benjamin M. Scirica, TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: bscirica{at}partners.org).
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Abstract
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Objectives: The purpose of this study was to assess the relationship between ischemia detected on continuous electrocardiographic (cECG) recording and cardiovascular outcomes after acute coronary syndrome (ACS).
Background: The small size of prior studies evaluating cECG prevented full evaluation of the risk associated with ischemia across subpopulations and compared with other methods of risk stratification. Ranolazine, a new antianginal agent, reduces ischemic symptoms in patients with chronic angina and after ACS but the anti-ischemic effect, as detected by cECG, is not known.
Methods: In all, 6,560 patients hospitalized with non–ST-segment elevation ACS were randomly assigned to ranolazine or placebo in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36) trial. The cECG was performed for 7 days after randomization. Outcomes were followed for a median of 348 days. Clinical events that occurred during cECG recording were excluded from analysis.
Results: A total of 6,355 (97%) patients had cECG recordings evaluable for ischemia analysis. Patients with  1 episode of ischemia on cECG (n = 1,271, 20%) were at increased risk of cardiovascular death (7.7% vs. 2.7%, p < 0.001), MI (9.4% vs. 5.0%, p < 0.001), and recurrent ischemia (17.5% vs. 12.3%, p < 0.001). The relationship with cardiovascular death was independent of baseline characteristics or elevated biomarkers (adjusted hazard ratio: 2.46, p < 0.001). Ischemia on cECG was associated with significantly worse outcomes in several subgroups. Ranolazine did not reduce the rate of ischemia detected on cECG (19.9% vs. 21.0%, hazard ratio: 0.93, p = 0.21).
Conclusions: In more than 6,300 patients with ACS, ischemia detected on cECG occurred frequently and was strongly and independently associated with poor cardiovascular outcomes, including cardiovascular death. Continuous ECG monitoring to detect ischemia after ACS may help to identify patients at increased risk. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes [MERLIN]; NCT00099788)
Key Words: acute coronary syndrome • ischemia • electrocardiography • Holter • ranolazine
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | BNP = B-type natriuretic peptide | | cECG = continuous electrocardiography | | HR = hazard ratio | | IQR = interquartile range | | MI = myocardial infarction | | NSTE = non–ST-segment elevation |
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Despite advances in pharmacological and interventional treatment of patients with acute coronary syndrome (ACS), recurrent ischemia may occur early after initial stabilization and is generally considered to be associated with poor cardiovascular outcomes (1). Continuous electrocardiographic (cECG) monitoring is a sensitive method to detect and quantify recurrent myocardial ischemia. Several prior studies found that ischemia as detected on cECG monitoring was associated with poor outcomes, but most such studies were performed before the widespread use of an interventional strategy and potent adjunctive antiplatelet and antithrombotic therapy (2–9). Moreover, the relatively small numbers of clinical events in these studies prevented a full examination of the association between cECG ischemia and clinical outcomes, particularly cardiovascular death, across relevant subpopulations and in comparison with other contemporary methods of risk stratification.
Ranolazine, a piperazine derivative, is a novel antianginal agent that reduces anginal frequency and improves exercise performance in patients with chronic stable angina (10–12) and reduces symptomatic recurrent ischemia after ACS (13). In this new analysis, we evaluated the association between ischemia as detected by cECG and clinical outcomes in a large contemporary cohort of patients admitted with non–ST-segment elevation (NSTE) ACS and determined whether ranolazine would reduce ischemia detected on cECG monitoring during the first week after admission.
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Methods
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In the MERLIN–TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36) trial, 6,560 patients hospitalized with NSTE ACS were randomly assigned to ranolazine or placebo in addition to standard medical and invasive therapy (14). Eligible patients had at least 10 min of ischemic symptoms at rest and presented with at least 1 of the following: elevated biomarkers of myonecrosis, ST-segment depression 0.1 mV, history of diabetes mellitus, or an intermediate to high TIMI risk score (3) and received randomized assignment within 48 h of their last ischemic symptoms in a blinded manner to intravenous ranolazine followed by oral ranolazine or matching placebo. Patients were stratified according to the treating physician's intent to treat the patient with an early invasive versus conservative treatment strategy. Full inclusion and exclusion criteria, as well as study procedures, have been published previously (13,14). Exclusion criteria relevant to this analysis include baseline ECG abnormalities including left bundle branch block, predominant ventricular paced rhythm, significant left ventricular hypertrophy, and concurrent digoxin use.
The primary end point of the MERLIN–TIMI 36 trial was the composite of cardiovascular death and recurrent ischemic events. A cECG (Holter) recording (Lifecard CF, DelMar Reynolds/Spacelabs, Issaqua, Washington) was to be performed for the first 7 days after randomization in all patients to assess for ischemia as part of a pre-defined efficacy analysis (13,14). Analysts and cardiologists blinded to treatment assignment and clinical outcomes performed ischemia analyses of all cECG recordings in the TIMI ECG Core Laboratory to detect any ischemic episode with 0.5 mm ST-segment depression lasting at least 1 min.
The primary ischemic end point of the cECG assessment was the incidence of ischemia defined as 1 mm ST-segment depression lasting at least 1 min with a heart rate at the onset of the episode <100 beats/min. Secondary cECG ischemic end points were pre-defined as episodes with 0.5 mm ST-segment depression lasting at least 1 min, and the incidence of ischemia occurring within 72 h of randomization. Ischemic burden was calculated from the sum of the area under the ST-segment trend curves for each ischemic episode (15).
All analyses comparing ischemia detected on cECG and clinical ischemic events excluded any component of the primary end point (cardiovascular death, new or recurrent myocardial infarction [MI], or symptomatic episode of recurrent ischemia) that occurred within the first 7 days during the time of cECG monitoring. A blinded clinical events committee adjudicated cardiovascular death, MI, and recurrent ischemia. The TIMI risk score was calculated using the previously described method and categorized as low (0 to 2), moderate (3 to 4), or high (>4) risk (16).
Blood samples were obtained at enrollment in 4,366 patients and analyzed in the TIMI Biomarker Core Laboratory (Boston, Massachusetts). B-type natriuretic peptide (BNP) was measured using the ADVIA Centaur (Siemens Medical Solutions, Malvern, Pennsylvania) (17) using a pre-specified decision limit of 80 pg/ml on the basis of our prior work (18). Levels of cardiac troponin-I were measured using the TnI-ultra assay (Siemens Medical Solutions), which has a 99th percentile decision limit of 0.04 ng/ml with a <10% coefficient of variation.
Statistical analysis.
All ischemia analyses were based on patients with evaluable cECG data. Continuous data were compared with a t test for normally distributed data and a Wilcoxon rank sum test for non-normally distributed data. Dichotomous variables were compared with a chi-square test (14). Hazard ratios (HRs) and 95% confidence interval (CI) were estimated using a Cox proportional hazards regression model. Clinical event rates are presented as Kaplan-Meier failure rates that were calculated beginning at day 8 after randomization though 1 year. Receiver-operator characteristic curves and c-statistics were generated for the different multivariable models that did and did not include ischemia detected on cECG. Differences between models were determined by comparing likelihood ratio values for each model. All analyses reported in this manuscript were performed independently by the TIMI Study Group using STATA/SE version 9.2 (STATA Corp., College Station, Texas) (13).
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Results
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Of the 6,560 patients in the MERLIN–TIMI 36 trial, 6,355 (97%) patients had cECG recordings that were interpretable for analysis. Continuous ECG monitoring was not performed in 105 (1.7%) patients and technical failures in the recording of the cECG prevented analysis of 100 (1.6%) recordings. The median duration of cECG recording was 6.0 days. A total of 39,340 patient-days (944,160 h) of cECG recordings was analyzed.
Incidence of ischemia on cECG.
Overall, 1,271 (20%) patients experienced at least 1 episode of ischemia on cECG. Among the 1,271 patients who experienced at least 1 episode of ischemia, the median number of episodes was 3 (interquartile range [IQR]: 1 to 7). A distribution of the number of ischemic episodes per day, the number of patients with an ischemic episode per day, and the number of patients with their first ischemic episode is presented in Figure 1. Two-thirds of patients had their first episode of ischemia within the first 48 h of cECG monitoring. Among patients who experienced ischemia, the median total duration of ischemia was 119 min (IQR: 43 to 354 min), and the median ischemic burden was –4,987 mV/min (IQR: –15,532 to –1,283 mV·min).
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Figure 1 Frequency of Ischemic Episodes Detected on cECG
Frequency of ischemic episodes by the day of continuous electrocardiographic (cECG) recording after randomization. The yellow bars represent the total number of ischemic episodes per day. The blue bars represent the number of patients who experienced at least 1 episode of ischemia per day, and the green bars represent the number of patients who experienced their first episode of ischemia per day.
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Clinical correlates and incidence of ischemia detected on cECG.
Baseline characteristics of the 6,355 patients with valid cECGs are presented in Table 1
according to whether they had ischemia on cECG or not. Patients with ischemia were more likely to be elderly, women, have impaired creatinine clearance or prior cardiovascular disease including hypertension, angina, or heart failure, and on presentation, were more likely to have had ST-segment depression, an elevated BNP or troponin, or high TIMI risk score. There was no difference in the rate of ischemia according to an invasive versus conservative strategy within the first 72 h after randomization (15.2% vs. 16.3%, p = 0.25), but there was a significantly lower rate of ischemia after 72 h (2.8% vs. 5.0%, p < 0.001) among patients for whom the treating physician selected an early invasive strategy.
Revascularization during the index procedure was more frequent among patients who had episodes of ischemia detected on cECG. There was similar if not higher use of antianginal therapy (beta-blockers, nitrates, or calcium antagonist) but less use of thienopyridines or statins in patients with an episode of ischemia detected on cECG compared with patients who had no episodes of ischemia detected.
Ischemia detected on cECG and clinical outcomes.
Patients with at least 1 episode of ischemia were at increased risk of each component of the primary end point, including cardiovascular death (Table 2). Patients with >2 episodes of ischemia were at even greater risk compared with patients who had only 1 or 2 episodes (Fig. 2).
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Figure 2 Ischemia Detected on cECG and Cardiac Outcomes
Cumulative incidence of cardiovascular death (A) and the primary end point of cardiovascular death, myocardial infarction (MI), or recurrent ischemia (B) according to the number of ischemic episodes detected on continuous electrocardiography (cECG). The red lines represent >2 episodes; the blue lines represent 1 to 2 episodes; the green lines represent no episodes. HR = hazard ratio.
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Table 3
presents both the incidence of ischemia within multiple subgroups and the associated risk of cardiovascular death and the primary end point. Patients with the highest incidence of cardiovascular death (>10%) included those with both high-risk clinical features (e.g., age >65 years, prior heart failure) in addition to ischemia detected on cECG. Conversely, the absence of ischemia in any of the following low-risk populations—low BNP, undetectable level of troponin, age <65 years, or low TIMI risk score—identified a cohort with a particularly low rate of cardiovascular death ( 2.5%). Even among patients with a relatively low absolute risk of cardiovascular death, the relative risk associated with ischemia on cECG was particularly high. For example, the HR for cardiovascular death was 3.8 for patients with normal ejection fraction but with ischemia on cECG (p for interaction = 0.012 compared with no ischemia) and 4.7 for patients with a BNP 80 pg/ml and ischemia detected on cECG (p for interaction = 0.049). In a very low clinical risk population (i.e., no ECG changes on admission, negative troponin, and BNP 80 pg/ml, n = 95), ischemia on cECG was still strongly associated with an increased risk of cardiovascular death (5.1% vs. 0.6%; HR: 5.2, 95% CI: 1.52 to 17.79, p = 0.008).
In a multivariable model that included clinical characteristics and biomarker data, ischemia detected on cECG continued to be strongly and independently associated with all clinical ischemic end points, including cardiovascular death (Table 4) The addition of ischemia on cECG to the multivariable model significantly increased the c-statistic from the receiver-operating curves for both cardiovascular death (0.81 vs. 0.79, p < 0.001) and the primary end point (0.62 vs. 0.61, p < 0.001).
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Table 4 Adjusted Risk of Cardiovascular Complications Associated With Clinical, Biochemical, and Electrocardiographic Features
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This relationship between ischemia and outcomes was consistent among patients who underwent a conservative management strategy (HR with ischemia: 3.0, 95% CI: 2.3 to 4.1, p < 0.001 for cardiovascular death, and HR: 1.8, 95% CI: 1.5 to 2.1, p < 0.001 for the primary end point) or an early invasive strategy (HR with ischemia: 2.2, 95% CI: 1.2 to 3.9, p = 0.008 for cardiovascular death, and HR: 1.6, 95% CI: 1.3 to 2.0, p < 0.001 for the primary end point).
Early versus late ischemia.
The association between ischemia on cECG and clinical outcomes was also similar if the first ischemic event occurred within the first 48 h after randomization (rate of cardiovascular death of 8.0% for patients with ischemia vs. 3.0% for patients with no ischemia, HR: 2.50, 95% CI: 1.88 to 3.32, p < 0.001; and for the primary end point, 27.8% vs. 18.7%, HR: 1.60, 95% CI: 1.38 to 1.86, p < 0.001), or if the first ischemic episode occurred >48 h after randomization (rate of cardiovascular death 7.2% with ischemia vs. 3.5% without ischemia, HR: 2.42, 95% CI: 1.68 to 3.48, p < 0.001; and for the primary end point, 29.8% vs. 19.2%, HR: 1.71, 95% CI: 1.41 to 2.07, p < 0.001).
Ischemia before and after revascularization.
A total of 2,494 (39.3%) patients underwent coronary revascularization during their index hospitalization. Of these, patients who experienced at least 1 episode of ischemia on cECG before revascularization (n = 422), were at increased risk of cardiovascular death (3.2% vs. 1.7%, HR: 2.3, 95% CI: 1.3 to 4.2, p = 0.004) or the primary end point (23.1% vs. 18.0%, HR: 1.4, 95% CI: 1.1 to 1.8, p = 0.004). Fewer patients had an ischemic episode on cECG after revascularization (n = 109), but the presence of ischemia on cECG was also associated with an increased risk of the primary end point (30.7% vs. 18.3%, HR: 1.8, 95% CI: 1.2 to 2.7, p = 0.002) and numerical, although nonsignificant, increase in the risk of cardiovascular death (3.8% vs. 1.9%, HR: 1.7, 95% CI: 0.62 to 4.8, p = 0.30).
Ischemia according to extent of coronary artery disease.
Among patients who underwent angiography (n = 3,789), there was a stepwise increase in the incidence of ischemia on cECG with a greater extent of coronary artery disease (defined as a lesion >50% stenosis) ranging from 10.4% for patients with no significant epicardial disease (n = 442), 12.3% for patients with 1-vessel disease (n = 1,063), 18.9% for 2-vessel disease (n = 954), and 28.0% for 3-vessel disease (n = 1,330). Even among patients with minimal epicardial disease (0- or 1-vessel disease), ischemia on cECG was associated with increased risk cardiovascular death (4.4% vs. 0.5%, HR: 6.1, 95% CI: 2.4 to 15.5, p < 0.001).
Among patients who after revascularization had no residual lesions >50% stenosis (n = 1361), the presence of at least 1 episode of ischemia on cECG was associated with a significantly greater risk of cardiovascular death (3.4% vs. 1.0%, HR: 3.3, 95% CI: 1.4 to 7.9, p = 0.006).
ST-segment elevation.
A total of 204 (3.2%) patients experienced at least 1 episode of ST-segment elevation >1 mm lasting >1 min, although many (40%) of these patients also experienced ST-segment depression. Compared with patients with no ST-segment deviation, patients with ST-segment elevation were not at greater risk of cardiovascular death (3.2% vs. 2.7%, HR: 1.3, 95% CI: 0.61 to 2.8, p = 0.51) and only slightly greater risk of the primary end point (25.7% vs. 17.9%, HR: 1.4, 95% CI: 1.03 to 2.0, p = 0.03).
Ischemic episodes of only 0.5 to 1.0 mm depression.
A total of 246 (3.9%) patients experienced only ischemic episodes limited to 0.5 to 1.0 mm of ST-segment depression. That degree of ST-segment depression alone was not associated with an increased risk of subsequent cardiovascular events compared with patients without any ischemia (2.9% vs. 2.6%, HR: 0.88, 95% CI: 0.39 to 2.00, p = 0.76 for cardiovascular death alone; and 17.1% vs. 17.7%, HR: 0.92, 95% CI: 0.66 to 1.26, p = 0.59 for the primary end point).
Effect of ranolazine on cECG ischemia.
Treatment with ranolazine did not reduce the incidence of the primary cECG ischemic end point of 1 mm of ST-segment depression lasting 1 min with a heart rate <100 beats/min (19.9% for ranolazine vs. 21.0% for placebo, HR: 0.93, 95% CI: 0.84 to 1.04, p = 0.21). However, ranolazine did result in a greater reduction in the incidence of a pre-specified secondary ischemic definition of ST-segment depression of 0.5 mm (23.5% vs. 26.2%, HR: 0.89, 95% CI: 0.81 to 0.98, p = 0.02) and, in an exploratory analyses, was numerically more pronounced when examining events that occurred >72 h after randomization (Fig. 3A) and among episodes that had a higher heart rate at the onset of the event (Fig. 3B). There was no difference in the effect of ranolazine on clinical outcomes among patients who did or did not experience ischemia on cECG (incidence of cardiovascular death 7.5% vs. 8.0%, HR: 1.08, 95% CI: 0.73 to 1.6, p = 0.71 for patients with ischemia, and 2.6% vs. 2.8%, HR: 0.83, 95% CI: 0.60 to 1.2, p = 0.28 for patients with no ischemia, p for interaction = 0.33; 26.5% vs. 30.3%, HR: 0.88, 95% CI: 0.71 to 1.1, p = 0.26 in patients with ischemia, and for the primary end point, 17.2% vs. 18.5%, HR: 0.92, 95% CI: 0.80 to 1.05, p = 0.22 for patients with no ischemia, p for interaction = 0.74).
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Figure 3 Effect of Ranolazine on Ischemia Detected on cECG
(A) The effect of ranolazine on ischemic episodes that occurred 72 h after randomization. Patients who had events during the first 72 h were included in this analysis. There was no statistical interaction between timing of the event and treatment with ranolazine. (B) The relationship between ischemic episodes and ranolazine according to the heart rate at the onset of ST-segment depression. cECG = continuous electrocardiographic monitoring; HR = hazard ratio.
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Discussion
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With more than 6,300 patients and almost 40,000 patient-days of recordings, this is the largest reported cECG or Holter assessment of patients with coronary artery disease. In this contemporary cohort of patients with NSTE ACS, recurrent ischemia as detected on cECG during the first week after hospitalization occurred frequently and was strongly associated with a higher risk of recurrent clinical events, including cardiovascular death beyond the first week. The poor prognosis associated with recurrent ischemia was observed in a population receiving contemporary interventional and pharmacologic therapy. Data regarding ischemic on cECG significantly improved the ability to identify patients at greatest risk in conjunction with standard risk stratification tools (e.g., clinical risk scores and biomarkers).
cECG for risk assessment after ACS.
In other studies of cECG from the past 2 decades, ischemia on cECG has been reported in 8% to 46% of patients admitted with ACS, depending on the clinical scenario and the duration of cECG recording (7). Several of the more recent and largest studies to date report an incidence of ischemia at 48 h between 15% and 25% (2,6,19). In the MERLIN–TIMI 36 trial, the rate of ischemia on cECG at 7 days was 20%, but <15% by 48 h, likely reflecting the more aggressive medical and interventional therapy given to patients in this study during the index hospitalization (13). Despite the high rate of utilization of guideline-recommended therapies, recurrent ischemia detected on cECG still occurred frequently, and when it did, carried a very poor prognosis, even among patients who would otherwise be considered low risk or among patients who had successful revascularization.
Prior studies of cECG in ACS have demonstrated an association between ischemia on cECG and clinical outcomes but have not had sufficient power to reliably examine cardiovascular mortality alone. In a meta-analysis that included 995 patients and 8,923 h of recording, recurrent ischemia on cECG was associated with the composite of death or MI (2). Another study of 681 patients with NSTE ACS found that ST-segment deviation discovered on 48-h cECG monitoring was associated with an increased risk of death and MI over the first 30 days after admission (6). Few studies, though, have demonstrated an independent relationship between ischemia on cECG and cardiovascular death alone, as observed in the MERLIN–TIMI 36 trial. In addition, prior studies of cECG were at most 48 h in duration and therefore captured only a short period of clinical events. The improvements in technology that permit 7 days of cECG monitoring demonstrate that late ischemic episodes continue to occur many days after admission and are associated with worse outcomes.
The large observation time during cECG monitoring in this study permitted us a more detailed evaluation of the clinical correlates of recurrent cECG ischemia than previously performed, a more thorough adjustment for other clinical risk indicators, and evaluation in conjunction with other tools for risk stratification. We found that the relationship between ischemia on cECG and clinical outcomes, including cardiovascular death, remained independent and consistent in important subgroups of clinical interest, and after comprehensive multivariable adjustment. Notably, ischemia on cECG significantly improved the prognostic discriminatory capacity (c-statistic) of clinical characteristics and biomarker data. This improvement contrasts with that from other tools for risk stratification, such as novel biomarkers (20) Furthermore, there were some populations in which the absence or presence of ischemia on cECG identified an especially low- or high-risk group. For example, patients with a normal level of BNP and no ischemia on cECG had a low (1.0%) incidence of cardiovascular death whereas the rate was 5.4% for patients with low BNP and evidence of ischemia on cECG. Moreover, there was a >10-fold higher incidence of cardiovascular death (12.1%) among patients who had both an elevated BNP and ischemia detected on cECG compared with patients who had normal BNP and no ischemia. A similar divergent and increased risk of cardiovascular death according to the presence of ischemia was also observed among patients >65 years old, with a history of MI or heart failure, or with an elevated troponin level or high TIMI risk score.
Ranolazine and cECG ischemia.
Ranolazine has been shown to reduce anginal frequency without clinically significant effects on the heart rate or blood pressure (10–12). In our study, ranolazine had a modest, nonsignificant effect on ischemia detected on cECG during the first 7 days after admission ACS. The effect was slightly greater using a broader definition of ischemia and when examining events that occurred several days after admission or events that were selected to be potentially demand related, occurring with a faster heart rate at onset.
Nevertheless, our findings indicate that during the acute phase of ACS, ranolazine does not exert a clinically relevant anti-ischemic effect as detected by cECG. These findings are consistent with the overall MERLIN–TIMI 36 trial in which there was a similar 8% reduction in symptomatic ischemia during the first 30 days after randomization among patients assigned to ranolazine. The lack of significant reduction in ischemia detected on cECG is in contrast, though, to both the long-term MERLIN–TIMI 36 findings with respect to recurrent symptomatic ischemia, where treatment with ranolazine resulted in 13% significant reduction in symptomatic recurrent ischemia (13), and in studies of patients with stable angina where treatment with ranolazine not only reduced angina but also prolonged time to ST-segment depression during exercise stress tests (10–12).
The divergent results from these 2 different clinical settings—the early phase of ACS versus chronic ischemic heart disease—may relate to the different predominant underlying etiologies of ischemia in these situations. During the initial presentation with ACS and plausibly during early recurrence, ischemia is principally driven by reduced myocardial oxygen supply due to stuttering atherothrombotic obstruction of epicardial coronary arterial flow; whereas after the successful treatment of ACS (and in the case of chronic angina) when the acute thrombus has dissipated, ischemia is more frequently due to increased oxygen demand exceeding the supply through fixed epicardial or small-vessel disease. Commensurate with this hypothesis, prior studies in which a reduction of ischemia on cECG was achieved used potent antiplatelet and antithrombin agents (4,8,19,21). Ranolazine, which is believed to predominately improve the "demand side" of ischemia would thus be more likely to benefit the treatment of chronic angina but less likely to modify the sudden ischemia from a rapidly growing thrombus. Even if ranolazine improves coronary perfusion by reducing left ventricular end-diastolic pressures, as suggested in animal models (22), it may not be able to compensate sufficiently to counteract an occlusive thrombus.
Study limitations.
We were unable to assess how many of the ischemic event captured on cECG were associated with clinical symptoms and thus cannot determine what proportion of ischemia was "asymptomatic" versus episodes also manifested by symptoms. However, to ensure that the relationship between ischemia on cECG and clinical outcomes was a true association and not simply due to "double-counting" of an ischemic event detected on cECG that also resulted in a component of the primary end point, we specifically excluded from our analysis any event that occurred during the period of cECG monitoring. If anything, this approach would weaken the association between ischemia on cECG and outcomes because we likely excluded some clinical events that occurred hours or days after the episode of cECG but still within the first 7 days of admission. In addition, the MERLIN–TIMI 36 trial excluded patients with significant baseline ECG abnormalities, and therefore these findings cannot be extended to all patients, such as those with significant repolarization abnormalities on the resting ECG. Given the neutral primary efficacy analysis of the main trial, the analyses of ranolazine and cECG ischemia must be regarded as exploratory in nature. The analyses of cECG ischemia by heart rate at onset were post-hoc for the purpose of exploring the mechanistic hypotheses articulated in the discussion.
For this clinical protocol, we modified standard cECG monitoring software to extend the recording time up to 7 days. While that is longer than the typical 24- or 48-h period used in clinical practice, we demonstrate that extended monitoring identifies many ischemic episodes that occur after 48 h and would therefore be missed with standard cECG recordings.
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Conclusions
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In accordance with current practice guidelines (23,24), cECG monitoring should be routinely performed for all patients admitted with ACS. In practice, though, clinical emphasis centers on the detection of arrhythmias, and regardless of the recommendations of some (25), less effort is focused on monitoring ST-segment deviation despite technologic advances that make such review easier to perform. Our data suggest that despite contemporary therapy with potent antiplatelet and antithrombotic therapy, including glycoprotein IIb/IIIa inhibitors and thienopyridines, and widespread use of revascularization, recurrent ischemia as detected on cECG remains frequent, and when it occurs, carries a poor prognosis. The detection of ischemia by cECG therefore provides incremental prognostic information with which to assess the risk of recurrent major cardiovascular events in patients after NSTE ACS.
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Footnotes
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Continuing Medical Education (CME) is available for this article. Go to http://cme.jaccjournals.org to participate.
The MERLIN-TIMI 36 study was supported by CV Therapeutics. The TIMI Study Group reports receiving significant research grant support from Accumetrics, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck & Co., Merck-Schering Plough Joint Venture, Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, and Schering-Plough. Dr. Scirica receives honoraria for consulting and educational presentations from CV Therapeutics, and is supported in part by an unrestricted research grant from Michael Lerner. Dr. Morrow receives honoraria for educational presentations from CV Therapeutics and Sanofi-Aventis, serves as a consultant for GlaxoSmithKline and Sanofi-Aventis, and is on the advisory board for Genentech. Dr. Budaj receives honoraria from CV Therapeutics, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Sanofi-Aventis, and serves as a consultant to GlaxoSmithKline and Sanofi-Aventis. Dr. Aroesty serves as a consultant to Fibrogen, which has no commercial products and is conducting no research that could bear any relationship to this paper. Dr. Stone receives a research grant from CV Therapeutics. Dr. Braunwald receives honoraria from and serves as a consultant to AstraZeneca, Bayer AG, CV Therapeutics, Daichii Sankyo, Merck, Pfizer, and Schering-Plough.
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