Relationship Between Nonsustained Ventricular Tachycardia After NonST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death: Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in NonST-Elevation Acute Coronary SyndromeThrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial Benjamin M. Scirica, Eugene Braunwald, Luiz Belardinelli, Chester M. Hedgepeth, Jindrich Spinar, Whedy Wang, Jie Qin, Ewa Karwatowska-Prokopczuk, Freek W.A. Verheugt and David A. Morrow Circulation 2010;122;455-462; originally published online Jul 19, 2010; DOI: 10.1161/CIRCULATIONAHA.110.937136 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 Copyright © 2010 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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Coronary Heart Disease Relationship Between Nonsustained Ventricular Tachycardia After Non–ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial Benjamin M. Scirica, MD, MPH; Eugene Braunwald, MD; Luiz Belardinelli, MD; Chester M. Hedgepeth, MD, PhD; Jindrich Spinar, MD; Whedy Wang, PhD, MPH; Jie Qin, MS; Ewa Karwatowska-Prokopczuk, MD; Freek W.A. Verheugt, MD; David A. Morrow, MD, MPH Background—Most studies examining the relationship between ventricular tachycardia (VT) after acute coronary syndrome and sudden cardiac death (SCD) were performed before widespread use of reperfusion, revascularization, or contemporary medical therapy and were limited to ST-elevation myocardial infarction. The incidence and prognostic implications of VT in patients with non–ST-elevation acute coronary syndrome receiving contemporary care have not been examined. Methods and Results—The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG recording was performed for the first 7 days after randomization and evaluated in a blinded core laboratory. SCD (n⫽121) was assessed over a median follow-up of 1 year. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. Compared with patients with no VT (n⫽2764), there was no increased risk of SCD in patients with only ventricular triplets (n⫽1978, 31.2%) (1.4% versus 1.2%); however, the risk of SCD was significantly greater in patients with VT lasting 4 to 7 beats (n⫽1172, 18.5%) (SCD, 2.9%; adjusted hazard ratio, 2.3; P⬍0.001) and in patients with VT lasting at least 8 beats (n⫽431, 6.8%) (SCD, 4.3%; adjusted hazard ratio, 2.8; P⫽0.001). This effect was independent of baseline characteristics and ejection fraction. VT occurring within the first 48 hours after admission was not associated with SCD. Conclusion—Nonsustained VT is common after admission for non–ST-elevation acute coronary syndrome, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788. (Circulation. 2010;122:455-462.) Key Words: acute coronary syndrome 䡲 antiarrhythmic drugs 䡲 death sudden 䡲 electrocardiography 䡲 ventricular tachycardia

V

entricular ectopy is frequent in patients hospitalized with acute coronary syndromes (ACS).1– 4 The clinical implications of nonsustained ventricular tachycardia (VT) after ACS remain uncertain, in particular relative to the risk of sudden cardiac death (SCD) in patients with shorter episodes of ventricular ectopy as well as the relationship between the timing of VT after hospital admission and prognosis. Most studies that investigated the incidence of

ventricular arrhythmias in the presence of ACS and the relationship with SCD focused on sustained VT and were carried out before widespread use of reperfusion, revascularization, or contemporary medical therapy.1,2,5 More recent studies include patients primarily with ST-elevated myocardial infarction (STEMI)6,7 and provide little information on the incidence of VT and the associated risk of SCD in the larger population of patients with non–ST-elevation ACS

Received September 17, 2009; accepted May 7, 2010. From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass (B.M.S., E.B., C.M.H., J.Q., D.A.M.); Gilead Science, Inc, Palo Alto, Calif (L.B., W.W., E.K.-P.); University Hospital Brno, Brno, Czech Republic (J.S.); and Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands (F.W.A.V.). Guest Editor for this article was David Siscovick, MD, MPH. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.937136/DC1. Correspondence to Benjamin M. Scirica, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail [email protected] © 2010 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.110.937136

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(NSTEACS), in whom continuous ECG monitoring is not generally recommended beyond 24 to 48 hours after admission. Consequently, the incidence of ventricular arrhythmias several days after NSTEACS and their clinical significance are not known.

Editorial see p 449 Clinical Perspective on p 462 The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial compared ranolazine, an antianginal agent that reduces myocardial ischemia via inhibition of the late phase of the inward sodium current (late INa),8,9 and placebo in patients with NSTEACS. In a prior work, we demonstrated that ranolazine reduced the incidence of cardiac arrhythmias detected on continuous ECG (cECG) monitoring.10 In our present analysis, we examine the association between VT after NSTEACS and the risk of SCD in a contemporary cohort of patients.

Methods In the MERLIN-TIMI 36 trial, 6560 patients hospitalized with NSTEACS were randomized within 48 hours of their last ischemic symptom to ranolazine or placebo in addition to standard medical and interventional therapy.11 The primary objective of the MERLINTIMI 36 trial was to assess the effect of ranolazine on the composite of cardiovascular death and recurrent ischemic events compared with placebo.11 A cECG recording (Lifecard CF, DelMar Reynolds/ Spacelabs, Issaqua, Wash) was to be performed for the first 7 days after randomization in all patients to assess for ischemia as part of an efficacy analysis and for arrhythmias as part of a safety analysis.11 The median time of cECG recording was 6.0 days. Arrhythmias were identified with a commercially available arrhythmia software program (Pathfinder, Spacelabs, Issaquah, Wash) that uses a combined automatic and interactive detection technique. All ventricular ectopic beats lasting at least 3 beats were reviewed and confirmed by analysts and cardiologists blinded to treatment assignment or outcome. Nonsustained VT was categorized according to current guidelines as at least 3 consecutive ventricular beats with a rate ⬎100 bpm.12 Episodes were further categorized according to a prespecified analysis plan as lasting only 3 (triplets), 4 to 7, and at least 8 consecutive beats. The timing of VT was available only for the longest episode lasting at least 8 beats. The mean clinical follow-up was 348 days. Using clinical narratives, hospital discharge summaries, and autopsy reports, a blinded clinical events committee adjudicated SCD, which was defined according to a previously described13 and accepted14 schema as a sudden, unexpected death that was either witnessed and occurred within 60 minutes from the onset of new symptoms and in the absence of a clear cause other than cardiovascular or unwitnessed and occurred within 24 hours of the individual being observed alive in the absence of preexisting progressive circulatory failure or other noncardiovascular causes of death.15 Brain natriuretic peptide (BNP) was measured in 4543 patients with the ADVIA Centaur (Siemens Medical Solutions, Malvern, Pa)16 in the TIMI Biomarker Core Laboratory (Boston, Mass) with a prespecified decision limit of 80 pg/mL based on our prior work.17 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. Left ventricular ejection fraction (LVEF) was reported by the investigators in 4428 patients.

Statistical Analysis All arrhythmia analyses were based on patients with evaluable cECG data. A total of 6345 patients (96.7%) had cECG recordings that were interpretable for analysis. cECG monitoring was not performed in 105 patients (1.6%), and technical failure prevented analysis of

Table 1. Frequency of Arrhythmia Detected on cECG Monitoring and the Associated Risk of SCD at 1 Year After Randomization VT No VT 3 beats (triplets) 4–7 beats ⱖ8 beats

Arrhythmia (n⫽6345), n (%)

SCD, %

HRadj* (95% CI)

P

2764 (43.6) 1978 (31.2) 1172 (18.5) 431 (6.8)

1.2 1.4 2.9 4.3

1.1 (0.67–1.8)† 2.3 (1.5–3.7)† 2.8 (1.5–5.1)†

0.74 ⬍0.001 0.0012

*Adjusted for TIMI Risk Score, prior myocardial infarction, prior heart failure, estimated creatinine clearance, and revascularization during index hospitalization. †Compared with patients with no VT.

110 recordings (1.7%). Baseline characteristics of the patients in the cECG substudy were well balanced between treatment groups and have previously been reported.10 Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with a Cox proportionalhazards regression model adjusted first for TIMI Risk Score, prior myocardial infarction, prior heart failure, estimated creatinine clearance (Cockcroft-Gault), and revascularization during index hospitalization and stratifying by the prerandomization intention to use an early invasive strategy.15 The model was then repeated with the inclusion of BNP and LVEF for patients who had them assessed. Rates of SCD are presented as Kaplan-Meier failure rates at 12 months. Estimates of the C statistic for the Cox regression models were calculated, and differences in C statistics after the addition of LVEF and the presence of VT to the clinical model were compared. The increased discriminative value of VT and left ventricular function was further examined with the method described by Pencina et al18 and calculated in R with Harrell’s program19 to determine the net reclassification improvement, which evaluates the degree of patients appropriately assigned to a higher or lower risk category, and integrated discrimination improvement, which evaluates the change in the estimated risk as a continuous variable. The relationship between the timing of VT and SCD was assessed with a test for linear trend with time. For this analysis alone, the “zero” time was set at hospital admission rather than the time of randomization. All analyses were performed by the TIMI Study Group using Stata 9.2 (Stata Corp, College Station, Tex). All authors have read and agree to the manuscript as written. The authors had full access to and take full responsibility for the integrity of the data.

Results Incidence of VT Ventricular arrhythmias detected on cECG during the first 7 days after randomization were frequent, with 3581 patients (56.4%) having at least 1 episode of VT lasting at least 3 beats. A total of 1978 patients (31.1%) had only episodes of VT lasting 3 consecutive beats (triplets), 1172 patients (18.4%) had an episode of VT lasting 4 to 7 beats, and 431 patients (6.8%) had an episode of VT lasting at least 8 beats (Table 1).

VT and SCD There were 121 cases of SCD. There was no significant difference in the risk of SCD between patients who had no episodes of VT and those with an episode of VT lasting only 3 beats (triplets) (1.2% versus 1.4%). However, the risk of SCD increased significantly among patients with an episode of VT lasting 4 to 7 beats (2.9%; HRadj, 2.3; 95% CI, 1.5 to 3.7; P⬍0.001) and in those patients with an episode of VT lasting at least 8 beats (4.3%; HRadj, 2.8; 95% CI, 1.5 to 5.1; P⫽0.001) compared with patients with no VT, even after adjustment for baseline clinical characteristics (Table 1 and Figure 1). In a sensitivity analysis, we excluded the 4 patients who died within 24 hours of VT and found a similar

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6 Risk vs. No Triplets or VT •Triplets - HR HR* 1.1 1 1 (0 (0.67-1.8), 67-1 8) p=0 p=0.74 74 •VT 4-7bts - HR* 2.3 (1.5-3.7), p<0.001 •VT >=8bts - HR* 2.8 (1.5-5.1), p=0.001

VT >= 8 beats (n=431)

Sudde en Cardiac Death (%)

* Adjusted for TIMI Risk Score, Prior MI, Prior HF, CrCl, revasc during index hospitaliza
on

4.3%

4

VT 4 -7 beats (n=1172)

2.9%

Triplets (VT=3 beats) (n=1978)

2

1 4% 1.4% No VT (n=2764)

1 2% 1.2%

Figure 1. Risk of SCD in patients with no ventricular ectopy, patients with ventricular triplets only, patients with the longest episode of VT of 4 to 7 beats, and patients with the longest episode of at least 8 beats. Patients with VT lasting 4 to 7 beats were at increased risk of SCD compared with patients with triplets only (HRadj, 2.13; 95% CI, 1.30 to 3.57; P⫽0.003), but there was no difference in risk compared with patients with VT lasting 8 beats (HRadj, 0.83; 95% CI, 0.45 to 1.56; P⫽0.59). MI indicates myocardial infarction; HF, heart failure; and CrCl, creatine clearance.

0 0 No. at Risk Placebo Ranolazine

200

400

Days from Randomiza
on 3184 3161

3023 2994

2647 2627

1964 1951

1167 1191

relationship compared with patients with no VT (SCD, 1.4%; HRadj, 1.1; 95% CI, 0.66 to 1.8; P⫽0.72 for triplets; SCD, 2.9%; HRadj, 2.3; 95% CI, 1.5 to 3.7; P⬍0.001 for VT lasting 4 to 7 beats; and SCD, 3.4%; HRadj, 2.2; 95% CI, 1.1 to 4.3; P⫽0.024 for VT lasting at least 8 beats). Other clinical variables that were independently associated with SCD in addition to VT included a high TIMI Risk Score, history of heart failure, no revascularization during the index event, and worsening renal function (Table 2). Among patients with a known LVEF (n⫽4428), both LVEF and VT were Table 2. Risk of SCD at 1 Year After Randomization According to Ventricular Arrhythmias and Clinical Variables Variables Model 1 (clinical variables) No VT or triplets VT 4–7 beats VT ⱖ8 beats Moderate TIMI Risk Score (3–4) High TIMI Risk Score (5–7) Revascularization during index event Creatinine clearance (per mL/h) Prior myocardial infarction History of heart failure Ranolazine Model 2 EF ⬍40% VT 4–7 beats VT ⱖ8 beats Model 3 BNP ⬎80 pg/mL VT 4–7 beats VT ⱖ8 beats

HRadj

95% CI

P

1.0 2.3 2.7 1.6 2.5 0.54 0.99 0.93 2.3 0.94

Referent 1.5–3.5 1.5–4.9 0.8–3.0 1.3–5.0 0.3–0.9 0.98–0.99 0.6–1.4 1.5–3.5 0.7–1.4

2.3 2.1 2.9

1.4–4.0 1.2–3.5 1.5–5.5

0.002 0.006 0.002

2.1 2.5 2.6

1.3–3.5 1.5–4.0 1.3–5.3

0.002 ⬍0.001 0.010

independently associated with SCD; the HRadj of SCD was 2.3 (95% CI, 1.4 to 4.0; P⫽0.002) for LVEF ⬍40%, 2.1 (95% CI, 1.2 to 3.5; P⫽0.006) for VT lasting 4 to 7 beats, and 2.9 (95% CI, 1.5 to 5.5; P⫽0.002) for VT lasting at least 8 beats. To evaluate the relationship between VT and SCD in a manner that removes any possible influence of ranolazine, we also examined the relationship between VT and SCD in patients assigned to placebo and found a relationship similar to that in the overall cohort (incidence of SCD, 1.2% in patients with no VT; 1.2% in patients with triplets [HRadj, 0.94; 95% CI, 0.45 to 1.9; P⫽0.86]; 2.9% in patients with VT lasting 4 to 7 beats [HRadj, 2.2; 95% CI, 1.2 to 4.2; P⫽0.014]; and 5.4% in patients with VT lasting at least 8 beats [HRadj, 3.7; 95% CI, 1.8 to 7.7; P⬍0.001]).

Discrimination and Reclassification ⬍0.001 ⬍0.001 0.15 0.009 0.022 ⬍0.001 0.72 ⬍0.001 0.76

The addition of LVEF to the clinical model improved the discrimination of risk for SCD based on an improved C statistic but did not significantly alter the integrated discrimination improvement. The addition of VT significantly improved both the C statistic and integrated discrimination improvement when added to the clinical model alone or when the clinical model also included LVEF. Both LVEF and the presence of VT significantly improved reclassification of patient’s risk of SCD. Specifically, the addition of VT to the clinical model alone improved reclassification (net reclassification improvement⫽0.392; P⬍0.001) with a similar improvement in reclassification when VT was added to the clinical model that also included left ventricular function (Table 3).

Risk of VT in High-Risk Subgroups

Model 1 includes all clinical variables listed. Models 2 and 3 include all clinical variables listed in Model 1 plus LVEF and BNP, respectively, among patients with those data.

Compared with patients with either no VT or triplets, the increased risk of SCD in patients with VT lasting 4 to 7 beats and lasting ⬎8 beats was also elevated among the subgroups of patients with and without prior myocardial infarction, prior heart failure, prolonged QTc (⬎450 milliseconds), elevated (⬎80 pg/mL) BNP, and reduced (LVEF ⬍40%) ventricular

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Table 3. Improvement in Discrimination and Reclassification With the Addition of LVEF and VT Clinical model Clinical model⫹LVEF ⬍40% P vs clinical model Clinical model⫹VT groups P vs clinical model Clinical model⫹LVEF ⬍40%⫹VT groups P vs clinical model⫹LVEF ⬍40%

C Statistic

NRI

IDI

0.73 0.76 ⬍0.001 0.76 ⬍0.001 0.77 ⬍0.001

0.283 0.012 0.392 ⬍0.001 0.392 ⬍0.001

0.196 0.00285 0.196 0.00936 0.004 0.00882 0.004

NRI indicates net reclassification improvement; IDI, improved discrimination index. VT groups: no VT/triplets, 4 to 7 beats of VT, and ⱖ8 beats of VT.

function (Figure 2). Among each subgroup, the absolute incidence of SCD was greater among patients who would be considered at highest risk (eg, prior heart failure, elevated BNP, or reduced ventricular function), but the relative hazard associated with VT lasting at least 8 beats was similar among all patients, even those who would be considered at lower risk. To evaluate further the relative risk of SCD associated with VT and the incremental prognostic information gained in conjunction with LVEF, we repeated the key analyses in only those patients with a known LVEF (Tables I through V in the online-only Data Supplement). Patients with a known LVEF tended to have slightly more comorbidities, but the rate of revascularization and use of ␤-blockers at discharge were similar in both groups. Overall, the risk of SCD associated with the presence of VT was similar in patients with known LVEF compared with the overall population.

Timing and Frequency of VT and Risk of SCD Among the 431 patients with an episode of VT lasting at least 8 beats, 87 patients (20.4%) had an episode within the first 24 hours after hospitalization, 93 (21.8%) had an episode between 24 to 48 hours, and 257 (57.9%) had an episode ⬎48 hours after hospital admission. The strength of the association between VT and SCD varied according to the timing of arrhythmia. Compared with patients with no VT, there was no associated increase in the risk of SCD for patients with an episode of VT lasting at least 8 beats that occurred within 24 hours of presentation (1.7% versus 1.5%; HR, 0.65; 95% CI, 0.09 to 4.6; P⫽0.66). VT lasting at least 8 beats that occurred between 24 to 48 hours after admission was also not associated with a statistically significant increase in risk of SCD. However, the risk increased significantly if the episode of VT lasting at least 8 beats occurred ⬎48 hours after admission (test for linear trend with time, P⫽0.001; Figure 3). In terms of the frequency of VT lasting at least 8 beats, 324 (75.2% of patients with VT lasting at least 8 beats) had one episode, 83 (19.3%) had 2–3 episodes, and 24 (5.6%) had more than three episodes. There was a stepwise increase in the risk of SCD with more frequent episodes of VT (1.6% in patients with no VT lasting 8 beats [referent], 3.8% [HR 1.9, 95% CI, 1.05–3.6, P⫽0.035] with one episode, 4.9% [HR 2.3, 95% CI 0.73–7.26, P⫽0.15] with 2–3 episodes, and 11.8% [HR 6.3, 95% CI 1.5–25.4, P⫽0.01] with more than three episodes).

Effect of Ranolazine on SCD in Patients With Ventricular Arrhythmias Among patients assigned to ranolazine, an episode of VT lasting at least 8 beats was not associated with SCD compared with patients with no VT lasting at least 8 beats (2.5% versus 1.6%; HR, 1.1; 95% CI, 0.3 to 3.5; P⫽0.90), whereas among patients assigned to placebo, VT lasting at least 8 beats was significantly associated with SCD (5.4% versus 1.5%; HR, 2.9; 95% CI, 1.6 to 5.3; P⫽0.001) (P for interaction⫽0.15). Among patients with an episode of VT lasting at least 8 beats, the rate of SCD was numerically lower in patients treated with ranolazine compared with those receiving placebo (2.5% versus 5.4%; HR, 0.36; 95% CI, 0.10 to 1.3; P⫽0.11). The association between VT lasting at least 8 beats and SCD in patients assigned to placebo remained significant even after adjustment for baseline characteristics and ejection fraction (HRadj, 2.8; 95% CI, 1.4 to 5.7; P⫽0.005). Among patients assigned to placebo with an episode of VT lasting at least 8 beats, the risk of SCD was time dependent over the follow-up period (P⫽0.036; Figure 4). The risk was greatest at 30 days (HRadj, 5.5; 95% CI, 4.6 to 6.4) and then gradually declined to an HRadj of 4.4 (95% CI, 3.4 to 5.3) at day 60, HRadj of 3.4 (95% CI, 2.4 to 4.5) at day 90, and HRadj of 2.3 (95% CI, 1.0 to 3.7) at day 138. There was no overall increased risk or time-dependent relationship in risk among patients with an episode of VT lasting at least 8 beat assigned to ranolazine.

Discussion

With ⬎6300 patients, the MERLIN-TIMI 36 trial is one of the largest evaluations of VT in patients with NSTEACS. We demonstrated that VT is common in the days after presentation and that even short episodes of ventricular ectopy of lasting 4 to 7 consecutive beats were independently associated with an increased risk of SCD and improved risk stratification for this complication over the subsequent year of follow-up. We also found that episodes of VT lasting at least 8 beats that occurred within 48 hours of admission were not associated with SCD, whereas those that occurred later significantly increased the risk of SCD. As expected and as previously reported,10 the absolute risk of SCD is greatest among those patients with other high-risk features (eg, a history of heart failure, prior myocardial infarction, or depressed LVEF); however, the presence of VT in these patients with other high-risk features identifies a group of patients with a particularly high 1-year risk of SCD. In addition, even among “low-risk” groups, the presence of VT was associated with an increased risk of SCD, even though the absolute rate was lower.

Ventricular Arrhythmias and Outcomes Results of a number of studies of acute myocardial infarction, the majority of which focused on STEMI, have shown that ventricular ectopic activity is common (40% to 70%) during hospitalization, with 5% to 10% of patients experiencing an episode of nonsustained VT.1–5,20 In patients with STEMI, there is conflicting evidence on the relationship between VT and subsequent SCD, with several earlier studies demonstrating an independent relationship between VT and cardiovascular complications1,5 and subsequent studies failing to find any relation-

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QTC<450 n=5117

SCD (%) 1.1 2.6 2.7

QTc >450 n=1190

2.0 4.3 10.0

1.0 (referent) 1.9 (0.9-4.2) 3.2 (1.3-7.7)

No Prior MI n=4136

1.1 2.1 27 2.7

1.0 (referent) 2.2 (1.2-3.9) 2 1 (0.8 2.1 (0 8-5 5.3) 3)

Prior MI n=2147

1.6 4.1 6.8

1.0 (referent) 2.4 (1.3-4.3) 3.3 (1.6-7.0)

No Prior HF 5277 n=5277

1.0 1.8 2.6

1.0 (referent) 1.8 ((1.0-4.1)) 1.7 (0.7-4.1)

Prior HF n=1068

2.3 8.7 12.2

1.0 (referent) 3.1 (1.7-5.9) 4.6 (2.0-10.3)

BNP <80 pg/ml n=2537

0.6 2.0 2 0 2.9

1.0 (referent) 2.6 2 6 (1.1-5.1) (1 1 5 1) 3.6 (1.0-12.5)

BNP >80 pg/ml n=1874

2.1 5.1 5.7

1.0 (referent) 2.2 (1.3-3.9) 2.2 (0.9-5.2)

EF >40% n=3894

12 1.2 2.1 3.1

1 0 (referent) 1.0 1.9 (1.1-3.6) 2.4 (1.0-5.6)

EF <40% n=385

2.8 6.1 12.2

1.0 (referent) 2.7 (1.0-8.0) 3.7 (1.2-11.4)

Ranolazine n=3161

1.3 3.0 2.5

1.0 (referent) 2.3 (1.2-4.2) 0.9 (0.2-4.0)

Placebo n=3184

1.2 2.9 5.4

1.0 (referent) 2.3 (1.3-4.0) 3.8 (1.9-7.5)

Subgroups

HRadj (95%CI) 1.0 (referent) 2.4 (1.5-3.8) 2.2 (1.0-4.8)

No VT/Trip VT 4-7 bts VT >=8 bts

0.5

459

0

VT worse

Figure 2. Incidence and risk of SCD according to episode of VT lasting 4 to 7 beats and at least 8 beats compared with patients with either no VT or triplets only among several subgroups. HR was adjusted for TIMI Risk Score, revascularization during index hospitalization, creatinine clearance, prior myocardial infarction (MI), and prior heart failure (HF). Event rates are from Kaplan-Meier estimates at 12 months. P⬎0.05 for interactions between the presence of VT, different subgroups, and the risk of SCD for all comparisons.

5

Adjusted HR ship, especially when left ventricular function was considered,4,21 although these findings have not been uniform.6,7,22 Relatively little information is available on nonsustained VT in patients with NSTEACS. Al-Khatib and colleagues23 pooled data from ⬎26 000 NSTEACS patients and found that sustained VT (lasting ⬎30 seconds) and ventricular fibrillation during the index hospitalization were both independently associated with short- and long-term mortality. Although large, this analysis did not include cECG recordings; thus, the relationship between the much more common episodes of nonsustained VT and outcomes could not be examined. In a study of 2130 patients with STEMI and non-STEMI, Ma¨kikallio and colleagues6 found that nonsustained VT was associated with SCD; however, the ECG recordings lasted only 24 hours and were performed up to 4 weeks after the index event. During the 7-day cECG monitoring in the MERLIN-TIMI 36 trial, more than half of all patients had at least 1 episode of ⱖ3 consecutive ectopic ventricular beats, almost a quarter experienced at least 1 episode of ⱖ4 ectopic beats, and almost 7% had an episode of VT lasting at least 8 beats. Although there was a minimal and nonsignificant increase in the risk of

SCD in patients with short episodes lasting 3 ventricular ectopic beats (triplets), the pattern of risk increased significantly in patients with longer episodes. Thus, detecting ventricular ectopy lasting at least 4 beats in patients with NSTEACS offers independent prognostic information on the risk of SCD. This finding is notable given that current ACS guidelines do not place great clinical significance on episodes of nonsustained VT. Our findings support the current recommendations that state that VT occurring within the 2 days after admission is not associated with SCD during long-term follow-up. Current guidelines, however, generally do not recommend ECG monitoring beyond 24 to 48 hours of hospitalization, especially for patients with NSTEACS. Hence, many of the episodes of VT that were detected in MERLIN-TIMI 36 during the prolonged monitoring that lasted up to 7 days after hospitalization would have been missed by the current standard-length in-hospital ECG monitoring. Extended use of cECG lasting up to 1 week after presentation, especially in high-risk subgroups, would identify patients at higher risk who may benefit from more intensive therapy. However,

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No VT >8 beats

Referent

<24 hours

0.63 (0.09-4.5)

24-48 hours

1.4 (0.3-5.6)

48-72 hours

3.7 (1.4-10.1)

>72 hours

2.9 (1.5-5.7)

0.01

0.1

1 Risk of SCD (HR)

10

Test for Linear Trend with Time p=0.001

Figure 3. Risk of SCD according to timing of VT lasting at least 8 beats and hospital admission.

further studies, including those from community-based populations, validating the incremental improvement in risk stratification based on the detection and timing of VT identified on extended (⬎48 hours) monitoring are needed.

Risk Associated With VT in Specific Subgroups Most clinical guidelines emphasize the importance of stratification according to high-risk features to identify patients at greatest risk of SCD.24 Reduced LVEF remains the most frequently used method to risk stratify patients for SCD. In our analysis, a depressed LVEF was independently associated with the risk of SCD. However, the magnitude of risk associated with depressed LVEF (HRadj, 2.3) is similar to that of VT (HRadj, 2.1 for VT 4 to 7 beats; HRadj, 2.9 for VT lasting at least 8 beats). The presence of VT lasting at least 4 beats significantly improved risk stratification of SCD as determined by integrated discrimination improvement and net reclassification improvement when added to a clinical model, even when LVEF was included. The consistency in the risk associated with VT was observed across several subgroups in both the high- and low-risk populations, including patients with and without preserved left ventricular function or prior heart failure. Thus, the presence of VT lasting at least 4 beats, even in a group of patients who would be considered low risk according to current risk stratification guidelines, still indicates a worse prognosis. An enduring paradox of the current risk stratification strategy that uses left ventricular function is that although patients with depressed systolic function are at greatest risk of SCD (and may benefit from placement of an implantable cardioverter-defibrillator), the vast majority of cases of SCD occur in patients with normal ventricular function. Moreover, even among patients determined to be at high risk on the basis LVEF, most guidelines recommend waiting several months until an implantable cardioverter-defibrillator is placed despite the fact that the risk of SCD is greatest during this time.12 How to address this risk remains a clinical dilemma. Two studies, the Defibrillator in Acute Myocardial Infarction (DINAMIT)25 and Immediate Risk Stratification Improves Survival (IRIS)26 trials, attempted to reduce the early risk of SCD after MI by randomizing patients to either immediate implantable cardioverter-defibrillator placement or medical therapy. Both found that defibrillators reduced arrhythmic deaths but increased nonarrhythmic death, resulting in an overall neutral effect on mortality.25,26 This finding highlights several important questions relevant to our analysis.

Figure 4. Risk of SCD according to time from randomization in patients with an episode of VT lasting at least 8 beats in patients assigned to placebo.

First, improved techniques to correctly identify patients at greatest risk remain a great clinical need. Our analysis in patients with NSTEACS extends the observation on the high, early risk of SCD in patients after ACS with depressed left ventricular function27 to a much larger patient population with predominantly preserved ventricular function but with evidence of VT on extended ECG monitoring. In our analysis, we demonstrate that integration of ECG data significantly improves the risk stratification of patients for SCD. The clinical implications of identifying these high-risk patients, however, remain uncertain and require further study. Second, modifying the risk of SCD with specific therapies remains elusive. One theory to explain the results of DINAMAT and IRIS was that implantable defibrillators reduce arrhythmic death only to permit patients to die soon thereafter of heart failure.28 The MERLIN-TIMI 36 cohort differed significantly from the DINAMIT and IRIS cohorts in that there were no STEMI patients and most patients had preserved left ventricular functions. In a population less likely to die of heart failure, reduction of arrhythmic death may not be counterbalanced by an increase in nonarrhythmic deaths. Third, implantable defibrillators may not be the optimal intervention in this patient population. The potential role of wearable automated defibrillators, subcutaneous leads, or therapies to reduce SCD requires prospective clinical trials in high-risk populations.

Ranolazine, VT, and SCD Our findings also suggest that ranolazine, an antianginal agent that reduces both the substrate and triggers of ventricular ectopy by preferentially inhibiting the late INa,8,29 may modify the subsequent risk of SCD among patients who had an episode of VT during the first days after admission for NSTEACS. We previously demonstrated that ranolazine significantly reduced the incidence of VT and found that this effect was also observed in several high-risk subgroups.10 We now extend this observation by comparing the relationship between VT and SCD among patients treated with ranolazine versus placebo. The risk of SCD associated with VT lasting at least 8 beats was observed in patients assigned to placebo, but it

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Scirica et al was not significant in the ranolazine group. Even though in the entire MERLIN-TIMI 36 cohort treatment with ranolazine did not result in a significant reduction in SCD and the interaction between VT lasting at least 8 beats, SCD, and treatment assignment did not achieve formal criteria for heterogeneity, our current findings in patients with VT raise the hypothesis that ranolazine may modify the subsequent risk of SCD associated with VT. In particular, the observed benefit of ranolazine in preventing SCD in patients with VT appears to be greatest during the first months after ACS, the time of greatest risk of SCD. Given the overall neutral results of the MERLIN-TIMI 36 trial, our observations on a potential interaction remain hypothesis generating and warrant prospective evaluation in future trials among patients at high risk for SCD.

Limitations As in all outcomes studies without implanted long-term monitors, one cannot determine the number of cases of SCD that were due to a lethal arrhythmia. However, the inadvertent adjudication of nonarrhythmic deaths as SCD would only weaken the observed relationship between arrhythmias and SCD. LVEF, which is the most common evaluation for risk stratification for SCD, was not available in all patients. However, among the ⬎4400 patients with LVEF, VT remained consistently and independently associated with SCD. We did not collect episodes of VT lasting ⬍3 beats, VT at a rate of ⬍100 bpm, the frequency of ventricular premature beats, or the timing of shorter episodes of VT, which limits the ability to interpret the clinical significance of these episodes.

Conclusions Nonsustained VT occurs frequently in patients hospitalized with NSTEACS and is independently associated with SCD, even in what would be considered a population at relatively low risk for SCD. The results of our study support the use of extended cECG monitoring beyond 48 hours after admission to detect the presence of even short episodes of VT lasting 4 beats to identify patients at highest risk for arrhythmic death.

Acknowledgments We would like to acknowledge Charles Contant, PhD, and Fang “Angela” Ren, both from the TIMI Study Group, for their additional statistical support.

Source of Funding MERLIN-TIMI 36 was supported by CV Therapeutics (now Gilead Science Inc).

Disclosures Dr Scirica reports having receiving honoraria for educational presentations from CV Therapeutics (now Gilead Sciences), Novartis, Merck, Schering-Plough, sanofi-aventis, Lilly, and Daiichi-Sankyo and has served as a consultant for AstraZeneca, Novartis, Cogentus, Gilead Sciences, and Shionegi. He is the recipient of unrestricted research grant from the Michael Lerner Foundation. Dr Braunwald has received honoraria for educational presentations and consulting from CV Therapeutics. Dr Verheugt reports having received educational and research grants from Bayer AG, Roche, Eli Lilly, and Boehringer Ingelheim and honoraria for consultancies from Pharmacia Upjohn, Eli Lilly, Merck, and Bayer (the Netherlands). Drs Belardinelli, KarwatowskaProkopczuk, and Wang are employees of and hold stocks/options in CV Therapeutics (now Gilead Sciences). Dr Hedgepeth reports having received honoraria from Johnson and Johnson. Dr Spinar reports having received grants from the Ministry of Education of the Czech Republic.

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Dr Morrow reports receiving honoraria for educational presentations from CV Therapeutics and sanofi-aventis, serving as a consultant for GlaxoSmithKline and sanofi-aventis, and being on an advisory board for Genentech. J. Qin reports no conflicts.

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CLINICAL PERSPECTIVE Nonsustained ventricular tachycardia (VT) occurs frequently in patients hospitalized with acute coronary syndromes, although the clinical implications of VT remain uncertain, in particular relative to the absolute risk of sudden cardiac death in patients with shorter episodes of ventricular ectopy and the relationship between the timing of VT after hospital admission and prognosis. In this study of ⬎6300 patients admitted with non–ST-elevation acute coronary syndrome and enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial who had 7-day continuous ECG monitoring, we found a ⬎2-fold increase in the risk of sudden cardiac death in patients with both short (4 to 7 beats in length) and longer (ⱖ8 beats in length) episodes of VT compared with patients with no VT. This relationship was unchanged after adjustment for clinical characteristics, including left ventricular ejection fraction and natriuretic peptides. In contrast, there was no increased risk of sudden cardiac death in patients with ventricular triplets. In regard to timing of VT, we found that only episodes occurring ⬎48 hours after admission were associated with an increased risk of sudden cardiac death, whereas earlier episodes within 48 hours did not carry the same risk. In several subgroups (history of heart failure, depressed ventricular function, QTc ⬎450 milliseconds), the presence of VT was associated with a ⬎10% incidence of sudden cardiac death at 1 year. The results of our study suggest that the use of extended continuous ECG monitoring beyond 48 hours after admission for non–ST-elevation acute coronary syndrome to detect the presence of even short episodes of VT may potentially identify patients at higher risk for sudden death.

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SUPPLEMENTAL MATERIAL

The Relationship between Non‐Sustained Ventricular Tachycardia Following Non‐ST  Elevation Acute Coronary Syndrome and Sudden Cardiac Death ‐   Observations from the MERLIN‐TIMI 36 Randomized Controlled Trial    Benjamin M. Scirica, MD MPH, Eugene Braunwald, MD, Luiz Belardinelli, MD,   Chester M. Hedgepeth MD PhD, Jindrich Spinar, MD, Whedy Wang PhD MPH,   Jie Qin, Ewa Karwatowska‐Prokopczuk, MD, Freek W. A. Verheugt, MD,    and David A. Morrow, MD MPH

 

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Supplemental Table 1  Baseline Characteristics and Incidence of VT and SCD in patients with known and  unknown Left Ventricular Function     

Known EF 

EF Unknown 

 (%) 

(%) 

 

 

 

Age > 75 

16.9 

18.7 

0.0713 

Female 

36.5 

32.0 

0.0005 

DM 

35.0 

31.56 

0.0065 

HTN 

76.8 

67.3 

<0.0001 

Hyperlipidemia 

67.0 

68.3 

0.3348 

Smoking 

25.0 

26.1 

0.3471 

Prior MI 

34.4 

33.7 

0.5776 

Prior PCI/CABG 

23.8 

32.5 

<0.0001 

Prior CHF 

18.3 

13.9 

<0.0001 

eGFR < 60 ml/min 

23.3 

24.4 

0.3340 

Index event = UA 

47.2 

45.9 

<0.0001 

Index event = NSTEMI 

51.3 

50.5 

Low TIMI Risk Score 

26.8 

26.9 

Moderate TIMI Risk Score 

53.0 

51.7 

High TIMI Risk Score 

20.2 

21.4 

Time from onset of pain to 

22.4 

25.8 

<0.0001 

Angio during index hosp 

60.5 

55.6 

0.0002 

Revasc during index Hosp 

39.5 

39.2 

0.8253 

D/C on BBl 

77.1 

78.8 

0.1324 

Baseline Characteristics and 

P value 

Treatment Strategies 

0.4958 

randomization median(IQR) 

 

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D/C on ACE‐I 

67.6 

58.4 

<0.0001 

 

 

 

 

Incidence of VT and SCD 

 

 

 

No VT/Triplets 

42.4 

45.9 

0.0234 

Triplets(VT=3bts) 

31.3 

30.9 

VT4‐7bts 

19.1 

17.1 

VT>=8 bts 

7.2 

6.1 

SCD 

1.9 

1.8 

0.8826 

   

 

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Supplemental Table 2  Frequency of Arrhythmia Detected on Continuous ECG Monitoring and the associated  risk of sudden cardiac death at 1 year after randomization among patients with known  left ventricular function     

 

 

N=4229 

SCD 

AdjHR* 

P  Arrhythmia 

value  (%) 

(%) 

(95%CI) 

Known LVEF  in   

 

 

 

No VT 

1815 (42.42%) 

1.25 

 

 

3 beats (triplets) 

1340 (31.32%) 

1.35 

0.97(0.53‐1.80) 

0.93 

4‐7 beats 

818 (19.12%) 

2.64 

2.22 (1.27‐3.89) 

0.005 

>= 8 beats 

306 (7.15%) 

4.72 

3.17 (1.59‐6.30) 

0.001 

Ventricular Tachycardia  

*Adjusted for TIMI Risk Score, prior myocardial infarction, prior heart failure, estimated  creatinine clearance, revascularization during index hospitalization  

 

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Supplemental Table 3  Risk of sudden cardiac death at 1 year following randomization according to ventricular  arrhythmias and clinical variables among patients with known left ventricular function    Adjusted  Variables 

 (95%CI) 

P value 

Hazard Ratio  No VT or Triplets 

1.0 

(referent) 

 

VT 4‐7 beats 

2.3 

1.4‐3.8 

0.0012 

VT >= 8 beats 

3.2 

1.7‐6.4 

<0.001 

Moderate TIMI Risk Score (3‐4) 

1.5 

0.7‐3.0 

0.29 

High TIMI Risk Score (5‐7) 

2.5 

1.1‐5.5 

0.029 

Revascularization during index event  

0.7 

0.4‐1.2 

0.16 

Creatinine Clearance (per ml/hr) 

0.99 

0.98‐0.99 

<0.001 

Prior myocardial infarction 

0.96 

0.6‐1.6 

0.87 

History of heart failure 

1.9 

1.2‐3.1 

0.011 

Ranolazine 

0.77 

0.5‐1.2 

0.25 

EF <40% 

2.3 

1.4‐4.0 

0.002 

 

 

 

2.3 

1.3‐4.3 

0.009 

In Patients with known BNP  BNP > 80 pg/ml 

 

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Supplemental Table 4  Improvement in Discrimination and Reclassification with the Addition of Left Ventricular  Ejection Fraction and Ventricular tachycardia among patients with known left  ventricular function     

C‐statistic 

NRI 

IDI 

Clinical Model 

0.782 

 

 

Clinical Model + LVEF <40% 

0.785 

0.0238 

0.000662 

NS 

P=0.862 

P=0.688 

0.802 

0.408 

0.0133 

<0.001 

P=0.003 

P=0.014 

0.802 

0.408 

0.013 

<0.001 

P=0.003 

P=0.013 

P value vs. clinical model  Clinical Model + VT groups  P value vs. clinical model  Clinical Model + LVEF <40% + VT groups  P value vs. clinical model + LVEF <40%  LVEF – left ventricular ejection fraction 

VT Groups (no VT/triplets, 4‐7 beats of VT, >=8 beats of VT) 

 

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Supplemental Table 5  Incidence and risk of sudden cardiac death in several patients subgroups with known  left ventricular function  Subgroup     QTC <450      QTC >=450      No prior MI      Prior MI      No Prior HF      Prior HF      BNP <=80 pg/ml      BNP> 80 pg/ml      EF ≥ 40%      EF < 40%      Ranolazine      Placebo     

 

Total Obs    3417      839      2780      1458      3498      781      1646      1293      3894      385      2123      2156     

SCD(%)    1.05  1.89  3.47  2.45  5.23  9.36  1.27  1.55  2.77  1.4  4.19  7.54  1.05  1.72  2.87  2.36  7.17  11.84  0.533  1  4.13  2.24  5.02  5.19  1.23  2.12  3.1  2.28  6.05  12.15  1.33  2.58  2.54  1.25  2.68  6.14 

label     No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts  No VT/Trip  VT 4‐7 bts  VT>=8 bts 

HRadj    1.0 (referent)  2.381  3.559  1.0 (referent)  1.823  2.335  1.0 (referent)  1.636  2.253  1.0 (referent)  3.125  4.584  1.0 (referent)  1.86  2.568  1.0 (referent)  3.034  4.577  1.0 (referent)  2.619  5.826  1.0 (referent)  2.237  2.225  1.0 (referent)  1.946  2.357  1.0 (referent)  2.792  3.659  1.0 (referent)  2.433  1.372  1.0 (referent)  2.036  3.984 

95% CI  Lower limit   Upper Limit  P Value        1.265  4.481  0.0072  1.546  8.192  0.0028        0.791  4.206  0.1589  0.832  6.55  0.1071        0.767  3.491  0.2031  0.783  6.479  0.1319        1.537  6.351  0.0016  1.956  10.741  0.0005        0.957  3.615  0.0673  1.056  6.243  0.0375        1.39  6.626  0.0053  1.762  11.892  0.0018        0.682  10.063  0.161  1.529  22.2  0.0098        1.134  4.41  0.0201  0.757  6.535  0.1458        1.065  3.557  0.0304  0.991  5.608  0.0525        0.973  8.008  0.0561  1.168  11.467  0.026        1.106  5.351  0.0271  0.32  5.887  0.6704        1.5  3.948  0.0353  1.868  8.499  0.0003 

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