We explored the utility of T-wave alternans (TWA) in predicting mortality in patients with non–ST-segment elevation acute coronary syndrome (NSTEACS). Maximum TWA was calculated using Modified Moving Average method from continuous electrocardiographic recordings in patients with left ventricular ejection fraction <40% and ventricular tachycardia (VT) ≥4 beats during index hospitalization or sudden cardiac death during the follow-up year and age- and sex-matched controls in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. All patients received standard therapy for NSTEACS plus ranolazine (n = 109) or placebo (n = 101). Median follow-up was 1 year. Baseline clinical characteristics did not differ between patients with elevated TWA (≥47 μV) compared with lower levels. Patients with TWA ≥47 μV at admission had increased risk of total mortality (adjusted odds ratio [OR adj ] 2.35, p = 0.04) during follow-up and VT ≥4 beats (OR adj 2.70, p = 0.01) during hospitalization with a trend toward increased cardiovascular death risk (OR adj 2.18, p = 0.07) during follow-up. In patients receiving placebo, TWA ≥47 μV on day 6 was associated with increased risk of total mortality (OR 4.12, 95% confidence interval 1.25 to 13.64, p = 0.02) and cardiovascular death (OR 4.73, p = 0.01) during follow-up. No deaths occurred among patients with TWA ≥47 μV assigned to ranolazine. In conclusion, in patients with NSTEACS and left ventricular ejection fraction <40%, TWA ≥47 μV early after admission is associated with increased risk of mortality at 1 year and with nonsustained VT during hospitalization. TWA may be useful in risk estimation in patients with NSTEACS. The possibility that TWA may serve as a therapeutic target deserves further exploration.
Microvolt T-wave alternans (TWA) is a useful predictor of cardiac events in patients with diverse ischemic and nonischemic pathologies with and without depressed ejection fraction. However, its utility in estimating risk in hospitalized patients with acute coronary syndrome (ACS), presenting with either acute myocardial infarction or unstable angina, has not been examined. This is an important missed opportunity given the incidence of ACS, which contributes to >1,141,000 hospitalizations annually in the United States and is associated with heightened risk for cardiac events after hospital discharge but with limited means for their prediction. The fact that patients with ACS are hospitalized for acute infarction precludes microvolt TWA assessment with exercise testing. The Modified Moving Average (MMA) method has been shown to be suitable for evaluating microvolt TWA from continuous electrocardiographic (cECG) recordings. The goal of the present study was to examine the association of microvolt TWA with mortality and ventricular arrhythmias in patients with non–ST-segment elevation acute coronary syndrome (NSTEACS) enrolled in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial.
Methods
The primary objective of the MERLIN-TIMI 36 trial was to assess the efficacy and safety of ranolazine (Gilead Sciences, Inc., Foster City, California). The study conformed to the guiding principles of the Declaration of Helsinki. The protocol was approved by the relevant institutional review boards at all participating centers. Written informed consent was obtained from all patients. Patients hospitalized with NSTEACS (n = 6,560) were randomized within 48 hours of their last ischemic symptom to ranolazine or placebo in addition to standard medical and interventional therapy. For the present substudy, TWA was analyzed in archived continuous electrocardiograms from 101 patients with left ventricular ejection fraction (LVEF) <40% and ventricular tachycardia (VT) ≥4 beats during hospitalization or sudden cardiac death (SCD) during 1-year follow-up along with a cohort of age- and sex-matched subjects from the remaining patients with LVEF <40% who did not experience VT or SCD. The analyses were performed in cECG recordings of 210 patients on day 1 and in all 156 available cECG records of these patients on day 6 to reflect a more convalescent phase. The end points of overall death, cardiovascular death, and SCD, a subcategory of cardiovascular death, during the subsequent year were adjudicated by an independent clinical events committee blinded to treatment allocation, and associations with TWA were analyzed. Associations of day 1 TWA with in-hospital 4-beat and 8-beat VT were analyzed because these events have been correlated with risk for SCD in the MERLIN trial.
Patients received either ranolazine (200 mg, intravenous; n = 109) or matching placebo (n = 101) over 1 hour followed by 80 mg/hour intravenous infusion, continuously for 12 to 96 hours. After completion of the infusion, ranolazine extended release or matching placebo was administered (1,000 mg twice daily) until the end of the study, except in cases of a protocol-specified reduction in dose, for example, for patients with new renal insufficiency or persistent QT interval prolongation.
cECG recordings (Lifecard CF; Del Mar Reynolds/Spacelabs, Issaquah, Washington) were made for the first 7 days after randomization in all patients. The median time of cECG recording was 6.0 days. Arrhythmias were identified using a commercially available arrhythmia software program (Pathfinder, Spacelabs, Issaquah, Washington) that uses a combined automatic and interactive detection technique. All ventricular ectopic beats lasting ≥3 beats were reviewed and confirmed by analysts and cardiologists blinded to treatment assignment and outcome. Nonsustained VT (NSVT) was categorized according to current guidelines as ≥3 consecutive ventricular beats at heart rates >100 beats/min. Episodes were further categorized according to a prespecified analysis plan as lasting only 3, 4 to 7, and at least 8 consecutive beats.
TWA was analyzed by investigators blinded to treatment assignment and outcomes throughout the 24-hour periods without atrial fibrillation on days 1 and 6 using the MMA method (GE Healthcare, Milwaukee, Wisconsin) in leads V 1 , V 5 , and aVF. The highest TWA level in any 15-second interval during sinus rhythm across the 24-hour periods was used for analysis of associations with events. The capacity to analyze recordings with changing heart rates makes the MMA method suitable for use during cECG monitoring. The established TWA cut point of 47 μV on continuous electrocardiography used in this study has been found to predict SCD and cardiovascular and total mortality from cECG records in patients with acute myocardial infarction or heart failure.
Patient selection and all statistical analyses were performed by the TIMI Study Group. Continuous data were compared with t test for normally distributed data and Wilcoxon rank sum test for non-normally distributed data. Dichotomous variables were compared using chi-square test. Because of the case-control method of selection, risk of death or ventricular arrhythmias was estimated using odds ratios adjusted for TWA ≥47 μV and elements of TIMI risk score.
Results
The study analyses in this subset of the MERLIN trial were performed in 101 cases with LVEF <40% and SCD during the 1-year follow-up or VT ≥4 beats during the index hospitalization along with 109 matched patients ( Table 1 ). The group with events comprised 95 patients with VT ≥4 beats and 16 with SCD, 10 of whom had also experienced ≥4-beat VT during hospitalization. During follow-up, a total of 34 patients died (16 patients receiving ranolazine [14.6%] and 18 receiving placebo [17.8%]), including 32 cardiovascular deaths (14 patients receiving ranolazine [12.8%] and 18 receiving placebo [17.8%]). A total of 40 patients (19.0%) had TWA at or above the recognized cut point of ≥47 μV at enrollment. More patients with elevated TWA and more patients with previous myocardial infarction experienced SCD or VT ≥4 beats than patients without these characteristics at baseline (p = 0.02 for both). Otherwise, baseline characteristics did not differ between patients with and without SCD or VT ≥4 beats. Median TWA was 35.0 μV (interquartile range [IQR] 28.0 to 43.0) on day 1 and was unchanged on day 6 (36.0 μV, IQR 27.0 to 46.0) in patients receiving either ranolazine or placebo. Patients with elevated (≥47 μV) versus low TWA (<47 μV) on day 1 did not differ with respect to baseline characteristics, details of presentation, index diagnosis, or baseline cardiac biomarkers ( Table 2 ).
| Patient Characteristics | Total (n = 210) | Sudden Cardiac Death or Ventricular Tachycardia ≥4 | p-Value | |
|---|---|---|---|---|
| Yes (n = 101) | No (n = 109) | |||
| T-wave alternans at day 1, median (interquartile range), μV | 35.0 (28.0–43.0) | 35.0 (29.0–47.0) | 34.0 (26.0–42.0) | 0.11 |
| T-wave alternans ≥47 μV | 40 (19%) | 26 (26%) | 14 (13%) | 0.02 |
| Treatment | 0.01 | |||
| Ranolazine arm | 109 (52%) | 40 (40%) | 69 (63%) | |
| Placebo arm | 101 (48%) | 61 (60%) | 40 (37%) | |
| Men | 145 (69%) | 74 (73%) | 71 (65%) | 0.20 |
| Age, median (interquartile range) (years) | 68.0 (58.0–75.0) | 68.0 (59.0–75.0) | 67.0 (58.0–75.0) | 0.66 |
| White | 201 (96%) | 96 (95%) | 105 (96%) | 0.75 |
| Body mass index, median (interquartile range) (kg/m 2 ) | 27.5 (24.7–30.1) | 28.0 (24.8–31.2) | 27.0 (24.7–29.4) | 0.14 |
| ST-segment depression ≥0.1 mV on baseline electrocardiogram | 95 (45%) | 49 (49%) | 46 (42%) | 0.36 |
| Diabetes mellitus | 88 (42%) | 36 (36%) | 52 (48%) | 0.08 |
| Hypertension | 160 (77%) | 75 (74%) | 85 (79%) | 0.45 |
| Current smoker | 52 (25%) | 29 (29%) | 23 (21%) | 0.20 |
| Prior myocardial infarction | 130 (63%) | 71 (70%) | 59 (55%) | 0.02 |
| Prior coronary revascularization | 77 (37%) | 37 (37%) | 40 (37%) | 0.96 |
| Heart failure | 76 (36%) | 36 (36%) | 40 (37%) | 0.87 |
| Renal disease | 72 (34%) | 33 (33%) | 39 (36%) | 0.64 |
| ST-segment deviation on baseline electrocardiogram | 134 (64%) | 68 (67%) | 66 (61%) | 0.31 |
| Index event type | 0.79 | |||
| Unstable angina pectoris | 79 (38%) | 39 (39%) | 40 (37%) | |
| Non–ST-elevation myocardial infarction | 128 (61%) | 60 (59%) | 68 (62%) | |
| Other | 3 (1%) | 2 (2%) | 1 (1%) | |
| Revascularization during index hospitalization | 94 (45%) | 45 (45%) | 49 (45%) | 0.95 |
| Creatine kinase, median (interquartile range), (IU/L) | 137.0 (81.0–256.0) | 150.0 (84.0–272.0) | 119.0 (74.0–226.0) | 0.41 |
| Creatine kinase myocardial type MB, median (interquartile range), (MCG/L) | 16.2 (7.4–40.6) | 17.0 (7.8–40.6) | 15.5 (6.0–38.5) | 0.51 |
| Elevated brain natriuretic peptide (>80 pg/mL) | 102 (75%) | 49 (78%) | 53 (73%) | 0.49 |
| N-terminal pro B-type natriuretic peptide, median (interquartile range), (pg/ml) | 184.0 (80.5–382.5) | 251.0 (99.0–417.0) | 162.0 (78.0–363.0) | 0.21 |
| Cardiac troponin I (cTnI), median (interquartile range), (MCG/L) | 0.2 (0.1–0.6) | 0.2 (0.1–0.4) | 0.2 (0.1–0.7) | 0.60 |
| Osteoprotegerin (ng/l) | 132 (63%) | 61 (60%) | 71 (65%) | 0.48 |
| Atrial fibrillation | 210 (100.0%) | 101 (100.0%) | 109 (100.0%) | — |
| No ventricular tachycardia or triplets | 50 (24%) | 3 (3%) | 47 (43%) | <0.01 |
| Ventricular tachycardia ≥4 beats | 95 (45%) | 95 (94%) | 0 (0%) | <0.01 |
| Ventricular tachycardia ≥8 beats | 36 (17%) | 36 (36%) | 0 (0%) | <0.01 |
| Cardiovascular death | 32 (15%) | 24 (24%) | 8 (7%) | <0.01 |
| Sudden cardiac death | 16 (8%) | 16 (16%) | 0 (0%) | <0.01 |
| Total death | 34 (16%) | 25 (25%) | 9 (8%) | <0.01 |
| Patient Characteristics | Total (n = 210) | T-Wave Alternans (μV) | p-Value | |
|---|---|---|---|---|
| <47 (n = 170) | ≥47 (n = 40) | |||
| Treatment | 0.66 | |||
| Ranolazine arm | 109 (52%) | 87 (51%) | 22 (55%) | |
| Placebo arm | 101 (48%) | 83 (49%) | 18 (45%) | |
| Men | 145 (69%) | 118 (69%) | 27 (68%) | 0.81 |
| Age, median (interquartile range) (years) | 68.0 (58.0–75.0) | 67.5 (57.0–75.0) | 68.0 (62.0–76.5) | 0.33 |
| White | 201 (96%) | 163 (96%) | 38 (95%) | 0.45 |
| Body mass index, median (interquartile range) (kg/m 2 ) | 27.5 (24.7–30.1) | 27.4 (24.7–30.1) | 28.1 (24.8–31.5) | 0.38 |
| ST-segment depression ≥0.1 mV on baseline ECG | 95 (45%) | 77 (45%) | 18 (45%) | 0.97 |
| Diabetes mellitus | 88 (42%) | 74 (44%) | 14 (35%) | 0.33 |
| Hypertension | 160 (77%) | 129 (76%) | 31 (78%) | 0.88 |
| Current smoker | 52 (25%) | 41 (24%) | 11 (28%) | 0.66 |
| Prior MI | 130 (63%) | 107 (63%) | 23 (59%) | 0.61 |
| Prior revascularization | 77 (37%) | 65 (38%) | 12 (31%) | 0.38 |
| Heart failure | 76 (36%) | 60 (35%) | 16 (40%) | 0.58 |
| Renal disease | 72 (34%) | 59 (35%) | 13 (33%) | 0.79 |
| ST-segment deviation on baseline ECG | 134 (64%) | 106 (62%) | 28 (70%) | 0.37 |
| Index event type | 0.57 | |||
| Unstable angina | 79 (38%) | 62 (36%) | 17 (43%) | |
| Non–ST-elevation MI | 128 (61%) | 105 (62%) | 23 (58%) | |
| Other | 3 (1%) | 3 (2%) | 0 (0%) | |
| Revascularization during index hospitalization | 94 (45%) | 81 (48%) | 13 (33%) | 0.08 |
| Creatine kinase, median (interquartile range), (IU/L) | 137.0 (81.0–256.0) | 134.0 (82.5–245.5) | 144.5 (74.0–367.0) | 0.72 |
| Creatine kinase myocardial type, MB, median (interquartile range), (MCG/L) | 16.2 (7.4–40.6) | 17.0 (6.8–40.3) | 15.0 (8.4–40.6) | 0.49 |
| Elevated brain natriuretic peptide (>80 pg/mL) | 102 (75%) | 86 (77%) | 16 (67%) | 0.30 |
| N-terminal pro B-type natriuretic peptide, median (interquartile range), (pg/ml) | 184.0 (80.5–382.5) | 184.0 (88.5–382.5) | 179.5 (65.5–380.0) | 0.68 |
| Cardiac troponin I (cTnI), median (interquartile range), (MCG/L) | 0.2 (0.1–0.6) | 0.2 (0.0–0.5) | 0.3 (0.1–0.9) | 0.18 |
| Osteoprotegerin (ng/L) | 132 (63%) | 109 (64%) | 23 (58%) | 0.44 |
| Atrial fibrillation | 210 (100%) | 170 (100%) | 40 (100%) | — |
| No VT or triplets | 50 (24%) | 42 (25%) | 8 (20%) | 0.53 |
| VT ≥4 beats | 95 (45%) | 69 (41%) | 26 (65%) | 0.01 |
| VT ≥8 beats | 36 (17%) | 28 (17%) | 8 (20%) | 0.59 |
| Cardiovascular death | 32 (15%) | 22 (13%) | 10 (25%) | 0.06 |
| Sudden cardiac death | 16 (8%) | 14 (8%) | 2 (5%) | 0.74 |
| Total death | 34 (16%) | 23 (14%) | 11 (28%) | 0.03 |
In this cohort of patients with NSTEACS and LVEF <40%, patients with TWA ≥47 μV at admission were at increased risk of total mortality (adjusted odds ratio [OR adj ] 2.35, 95% confidence interval [CI] 1.03 to 5.37, p = 0.04) and cardiovascular death (OR adj 2.18, 95% CI 0.93 to 5.11, p = 0.07) at 1 year and VT ≥4 beats (OR adj 2.70, 95% CI 1.31 to 5.56, p = 0.01) during the index hospitalization after adjustment for elements of the TIMI risk score ( Table 3 ).
