Ranolazine For Less Ischemia Research Articles

Plasma Omega-3 Fatty Acids and the Risk of Cardiovascular Events in Patients After an Acute Coronary Syndrome in MERLIN-TIMI 36.

BackgroundPlasma omega‐3 polyunsaturated fatty acids (ω3‐PUFAs) have been shown to be inversely correlated with the risk of cardiovascular death in primary prevention. The risk relationship in the setting of an acute coronary syndrome is less well established.Methods and ResultsBaseline plasma ω3‐PUFA composition (α‐linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) was assessed through gas chromatography with flame ionization detection in a case‐cohort study involving 203 patients with cardiovascular death, 325 with myocardial infarction, 271 with ventricular tachycardia, and 161 with atrial fibrillation, and a random sample of 1612 event‐free subjects as controls from MERLIN‐TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST‐Elevation‐Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36), a trial of patients hospitalized with non–ST‐segment–elevation ‐acute coronary syndrome. After inverse‐probability‐weighted multivariable adjustment including all traditional risk factors, a higher relative proportion of long‐chain ω3‐PUFAs (eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid) were associated with 18% lower odds of cardiovascular death (adjusted [adj] odds ratio [OR] per 1 SD, 0.82; 95% CI, 0.68–0.98) that was primarily driven by 27% lower odds of sudden cardiac death (adj OR per 1 SD, 0.73; 95% CI, 0.55–0.97). Long‐chain ω3‐PUFA levels in the top quartile were associated with 51% lower odds of cardiovascular death (adj OR 0.49; 95% CI, 0.27–0.86) and 63% lower odds of sudden cardiac death (adj OR, 0.37; 95% CI, 0.16–0.56). An attenuated relationship was seen for α‐linolenic acid and subsequent odds of cardiovascular (adj OR, 0.92; 95% CI, 0.74–1.14) and sudden cardiac death (adj OR, 0.91; 95% CI, 0.67–1.25). No significant relationship was observed between any ω3‐PUFAs and the odds of cardiovascular death unrelated to sudden cardiac death, myocardial infarction, atrial fibrillation, or early post‐acute coronary syndrome ventricular tachycardia.ConclusionsIn patients after non–ST‐segment–elevation‐acute coronary syndrome, plasma long‐chain ω3‐PUFAs are inversely associated with lower odds of sudden cardiac death, independent of traditional risk factors and lipids.RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00099788.

Effects of Ranolazine in Patients With Chronic Angina in Patients With and Without Percutaneous Coronary Intervention for Acute Coronary Syndrome: Observations From the MERLIN-TIMI 36 Trial.

Ranolazine, a piperazine derivative with anti-ischemic effects, reduces the frequency of angina and improves exercise performance in patients with chronic angina. The effects of ranolazine in patients with established ischemic heart disease and chronic angina undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) is not well described. We hypothesized that ranolazine would reduce ischemic events, regardless of revascularization. We examined the 1-year incidence of recurrent cardiovascular (CV) events in the subgroup of patients with prior chronic angina (n = 3565) enrolled in the randomized, double-blind, placebo-controlled Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation ACS (MERLIN)-Thrombolysis In Myocardial Infarction (TIMI) 36 trial who did or did not have a PCI within 30 days of the index event. Ranolazine reduced the risk of recurrent ischemia following admission regardless of whether patients had (hazard ratio [HR], 0.69; 95% confidence interval [CI] 0.51-0.92] or did not have PCI (HR, 0.81; 95% CI, 0.66-0.99; P interaction = 0.39). CV death, myocardial infarction, and recurrent ischemia were similarly lower with ranolazine in the PCI group (HR, 0.71; 95% CI, 0.55-0.91) vs the non-PCI group (HR, 0.91; 95% CI, 0.78-1.06; P interaction = 0.10), with a nominally significant decrease in CV death (HR, 0.39; 95% CI, 0.16-0.93) in the PCI group vs no difference in the non-PCI group (HR, 1.19; 95% CI, 0.89-1.59; P interaction = 0.02). In patients with chronic angina, ranolazine reduced recurrent ischemic events, regardless of whether patients did or did not receive PCI within 30 days of a non-ST-segment ACS.

Update on ranolazine in the management of angina.

Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome)-TIMI (Thrombolysis In Myocardial Infarction) 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost-effective due to its ability to decrease angina-related hospitalizations and improve quality of life.

ECG Morphological Variability in Beat Space for Risk Stratification After Acute Coronary Syndrome

BackgroundIdentification of patients who are at high risk of adverse cardiovascular events after an acute coronary syndrome (ACS) remains a major challenge in clinical cardiology. We hypothesized that quantifying variability in electrocardiogram (ECG) morphology may improve risk stratification post‐ACS.Methods and ResultsWe developed a new metric to quantify beat‐to‐beat morphologic changes in the ECG: morphologic variability in beat space (MVB), and compared our metric to published ECG metrics (heart rate variability [HRV], deceleration capacity [DC], T‐wave alternans, heart rate turbulence, and severe autonomic failure). We tested the ability of these metrics to identify patients at high risk of cardiovascular death (CVD) using 1082 patients (1‐year CVD rate, 4.5%) from the MERLIN‐TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non‐ST‐Elevation Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 36) clinical trial. DC, HRV/low frequency–high frequency, and MVB were all associated with CVD (hazard ratios [HRs] from 2.1 to 2.3 [P<0.05 for all] after adjusting for the TIMI risk score [TRS], left ventricular ejection fraction [LVEF], and B‐type natriuretic peptide [BNP]). In a cohort with low‐to‐moderate TRS (N=864; 1‐year CVD rate, 2.7%), only MVB was significantly associated with CVD (HR, 3.0; P=0.01, after adjusting for LVEF and BNP).ConclusionsECG morphological variability in beat space contains prognostic information complementary to the clinical variables, LVEF and BNP, in patients with low‐to‐moderate TRS. ECG metrics could help to risk stratify patients who might not otherwise be considered at high risk of CVD post‐ACS.

Prognostic Performance of Multiple Biomarkers in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome: Analysis From the MERLIN–TIMI 36 Trial (Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36)

The aim of this study was to assess the prognostic performance of C-terminal provasopressin (copeptin), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease. We measured copeptin, MR-proADM, and MR-proANP concentrations in 4,432 patients with NSTE-ACS who were randomized to treatment with ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36) trial and followed up for 1 year. A high concentration (quartile 4 vs. quartiles 1 to 3) of each biomarker identified an increased risk of CV death or HF(copeptin: 13.2% vs. 5.0%, p < 0.001; MR-proADM: 15.8% vs. 4.1%, p < 0.001; MR-proANP: 17.7% vs. 3.5%, p < 0.001)as well as CV death, HF, and myocardial infarction individually (all p ≤ 0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratio: copeptin, 1.71; MR-proADM, 1.96; MR-proANP, 2.20; all p ≤ 0.001).These biomarkers improved prognostic discrimination and patient re-classification for CV death or HF at 1 year(all categorical NRI >10%, p < 0.001), and maintained independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus BNP, cTnI, ST2, PAPP-A, and MPO (each p≤0.01) [corrected]. Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788).

Clinical Features, Use of Evidence‐Based Therapies, and Cardiovascular Outcomes Among Patients With Chronic Kidney Disease Following Non–ST‐Elevation Acute Coronary Syndrome

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular events following acute coronary syndrome (ACS). The underlying pathobiology and optimal treatments for this population continue to be evaluated. Patients with CKD will receive fewer evidence-based therapies and experience high rates of adverse cardiovascular events in both the short- and long term. The MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36) trial randomized non-ST-elevation ACS patients to ranolazine or placebo, with no exclusion for renal dysfunction (except dialysis). We conducted a prespecified analysis among 6543 patients based on the degree of CKD. Patients with worse renal function were older with more comorbidities (P < 0.0001 for each). They were less likely to receive evidence-based cardiovascular medicines (P < 0.04 for each). Rates of an early invasive management strategy varied based on renal function; however, among patients with the highest TIMI risk scores, the rates of an early invasive management strategy were similar regardless of glomerular filtration rate (GFR) (Pinteraction = 0.005). Lower GFR was associated with increased rates of cardiovascular disease or myocardial infarction in the short and long term, even after adjustment (GFR <30 vs ≥90 mL/min/1.73 m(2) ; hazard ratio [HR]: 3.24 [95% confidence interval {CI}: 1.26-8.38] through 7 days and HR: 2.12 [95% CI: 1.33-3.39] through 1 year). The effect of ranolazine vs placebo on clinical outcomes was similar among those with and without CKD (Pinteraction = not significant). Following ACS, patients with renal dysfunction had more cardiovascular risk factors but were less likely to receive evidence-based medical therapies. A strong graded, independent relationship between the degree of CKD and poor clinical outcomes was observed over time. Continued efforts to optimize ACS treatment strategies in patients with CKD are warranted.

Ranolazine's sweet side – improvement of glycaemic control by the novel mechanism of skeletal muscle microvascular recruitment

Type II diabetes mellitus is a major public health problem afflicting in excess of 250 million individuals worldwide. The presence of this condition in patients with coronary artery disease more than doubles their risk for cardiovascular events. Among the most critical factors are the attendant development of endothelial dysfunction and insulin resistance, which contribute to impaired glycaemic control and acceleration of atherosclerosis. Contemporary therapies have important limitations and safety concerns, as treatment with agents in extensive clinical use, including β-adrenergic receptor blocking agents, thiazide diuretics, and calcium channel antagonists, is associated with increased rates of newly diagnosed diabetes as a result of pro-diabetic effects. These limitations have prompted a search for alternative modalities of drug action. In the current issue of The Journal of Physiology, Fu and colleagues (2013) explored whether ranolazine can improve blood flow and distribution of insulin through α-adrenergic receptor-mediated vasodilatation. Ranolazine is a weak competitive antagonist of α-adrenergic receptors (Allely et al. 1993) and in the conscious dog this antagonism is unmasked by activation of the autonomic nervous system (Zhao et al. 2011). Fu and colleagues (2013) reported that in the therapeutic range of doses ranolazine recruited muscle microvasculature, resulting in a significant >2-fold increase in skeletal muscle blood flow and volume and a substantial enhancement of insulin-mediated whole-body disposal in the range of 30%. In addition, ranolazine improved delivery of insulin into skeletal muscle. Ranolazine increased endothelial nitric oxide synthase (eNOS) phosphorylation and cyclic adenosine monophosphate (cAMP) production without affecting endothelial insulin uptake. Isolated phenylephrine pre-constricted arterial rings were relaxed in the presence of ranolazine, indicating an α-adrenergic receptor-mediated effect. This observation is consistent with evidence obtained in vivo in which the vasoconstrictor effect of intracoronary phenylephrine was abolished by ranolazine (Nieminen et al. 2011) and the vasopressor response to methoxamine was blunted by ranolazine in a dose-dependent manner (Wang et al. 2008). Fu and colleagues (2013) also found that the vasodilatory effects on the pre-capillary arterioles occurred via actions on both the endothelium and smooth muscle cells. Overall, their observations indicate that at therapeutic concentrations ranolazine acutely recruits skeletal muscle microvasculature, increasing microvascular exchange surface area and perfusion. This effect, in combination with the drug's α-adrenergically mediated vasodilatation of pre-capillary arterioles, improves insulin delivery to skeletal muscle and glucose use. This intriguing study by Fu and coworkers (2013) raises important questions relevant to potential clinical applications. As the present studies were performed on an acute basis in normal rats, it remains to be determined whether microvascular recruitment persists following chronic administration in a diabetic animal model. Also, is there evidence that this action of ranolazine on muscle microvasculature operates in patients with various degrees of insulin resistance and early and late stage type 2 diabetes? Clinical trials have demonstrated that ranolazine significantly improves glycaemic control as suggested by reduced levels of glycated haemoglobin (HbA1c) in diabetic as well as non-diabetic subjects (Timmis et al. 2006; Morrow et al. 2009; Chisholm et al. 2010; Kosiborod et al. 2013). Use of ranolazine is also attractive in light of the excellent safety profile shown in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in NonST-Elevation Acute Coronary Syndromes Thrombolysis in Myocardial Infarction 36) trial, which enrolled 6560 patients with cardiovascular disease, 2028 (31%) of whom had pre-existing diabetes (Morrow et al. 2009). However, the mechanisms whereby ranolazine reduces HbA1c remain unknown. The clinical implications of this study are multifold and significant. Essentially, the authors have identified mechanisms that may underlie ranolazine's unique salutary effects, which can potentially improve the cardiovascular health of diabetic patients while reducing myocardial ischaemic events and risk for atrial and ventricular arrhythmias. Although considerable further work will be required to assess fully the clinical applicability of Fu and coworkers’ novel findings (2013), available clinical evidence suggests that the basic concept presented in the current study is promising and worthy of vigorous pursuit.

Inducible Fast Ventricular Tachycardia After ST-Segment–Elevation Myocardial Infarction

Although our understanding of sudden cardiac death (SCD) is far from complete, at least part of SCD post–myocardial infarction (MI) is because of ventricular tachycardia (VT) that degenerates to ventricular fibrillation. Because of the poor outcome of resuscitative efforts, considerable effort has been directed at risk stratification to guide interventions to prevent and to protect patients from this syndrome. Several clinical and laboratory variables (structural, arrhythmic, and autonomic) have been associated with poor outcome; how to use these to determine which patients are likely to have SCD, for which we have an established primary prevention treatment strategy, versus non-SCD remains elusive. Article see p 884 Ventricular ectopy was first recognized as a predictor of death in 1969; ventricular ectopy recorded on a standard ECG in outpatients were associated with a 6-fold increase in sudden death.1 For patients with early post-MI, Lown et al2 postulated that an electric catastrophe is more likely when ventricular premature beats occur early in the cycle, in salvos of ≥2, when they are multiform, or with a frequency >5/min. Ruberman et al3 showed that complex premature beats were associated with a risk of sudden coronary death 3× that for men free of these findings. A graded prognostic importance of ventricular premature beats and left ventricular dysfunction was described in the Myocardial Post-Infarction Program.4 The risk of nonsustained VT lasting 4 to 7 beats in the setting of acute coronary syndromes persists today as shown in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) study.5 Programmed electric stimulation (PES) arose as a way of mimicking spontaneous ectopy and subjecting it to formal study. The pioneering work of Wellens, Josephson and others suggested that inducibility indicated reentry as a mechanism of VT …

Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes

This study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). PAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality. We measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 μIU/ml was chosen from pilot work in this cohort. PAPP-A >6.0 μIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 μg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine. PAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications.

Role of ST2 in Non–ST-Elevation Acute Coronary Syndrome in the MERLIN-TIMI 36 Trial

We investigated the prognostic performance of ST2 with respect to cardiovascular death (CVD) and heart failure (HF) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) in a large multinational trial. Myocytes that are subjected to mechanical stress secrete ST2, a soluble interleukin-1 receptor family member that is associated with HF after STE-ACS. We measured ST2 with a high-sensitivity assay in all available baseline samples (N=4426) in patients enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in the Non-ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36), a placebo-controlled trial of ranolazine in NSTE-ACS. All events, including cardiovascular death and new or worsening HF, were adjudicated by an independent events committee. Patients with ST2 concentrations in the top quartile (>35 μg/L) were more likely to be older and male and have diabetes and renal dysfunction. ST2 was only weakly correlated with troponin and B-type natriuretic peptide. High ST2 was associated with increased risk for CVD/HF at 30 days (6.6% vs 1.6%, P<0.0001) and 1 year (12.2% vs 5.2%, P<0.0001). The risk associated with ST2 was significant after adjustment for clinical covariates and biomarkers (adjusted hazard ratio CVD/HF 1.90, 95% CI 1.15-3.13 at 30 days, P=0.012; 1.51, 95% CI 1.15-1.98 at 1 year, P=0.003), with a significant integrated discrimination improvement (P<0.0001). No significant interaction was found between ST2 and ranolazine (Pinteraction=0.15). ST2 correlates weakly with biomarkers of acute injury and hemodynamic stress but is strongly associated with the risk of HF after NSTE-ACS. This biomarker and related pathway merit further investigation as potential therapeutic targets for patients with ACS at risk for cardiac remodeling.

Myocardial Ischemia and Ventricular Tachycardia on Continuous Electrocardiographic Monitoring and Risk of Cardiovascular Outcomes After Non–ST-Segment Elevation Acute Coronary Syndrome (from the MERLIN-TIMI 36 Trial)

Among patients with non-ST-segment elevation acute coronary syndromes, recurrent ischemia and ventricular arrhythmias detected on continuous electrocardiographic monitoring remain common events that are associated with worse outcomes. The relative clinical significance of both events together is not well described. We determined the risk associated with ischemia (≥1 mm ST depression lasting ≥1 minutes) and ventricular tachycardia (VT) (≥4 beats) detected on 7-day continuous electrocardiographic monitoring in 6,355 patients with non-ST-segment elevation acute coronary syndromes from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. The patients were categorized into 4 groups according to the presence or absence of VT and ischemia. Cardiovascular death, sudden cardiac death (SCD), myocardial infarction, and recurrent ischemia were assessed during a median follow-up of 348 days. A total of 60.0% patients had no VT or ischemia, 20.0% had VT alone, 14.7% had ischemia alone, and 5.3% had both. The patients with either VT or ischemia were at increased risk of cardiovascular outcomes. The combination of ischemia and VT identified a particularly high-risk population for cardiovascular death (10.1% vs 3.0%, p <0.001), SCD (7.8% vs 0.9%, p <0.001), and myocardial infarction (15.4% vs 6.2%, p <0.001) compared to patients with neither. The addition of arrhythmia and ischemia significantly improved the clinical model for predicting cardiovascular death or SCD (p <0.001). In patients with both ischemia and VT, 66.6% of SCD occurred within 90 days of the non-ST-segment elevation acute coronary syndromes. In conclusion, in >6,300 patients with non-ST-segment elevation acute coronary syndromes, the presence of myocardial ischemia or VT alone, and particularly in combination, was independently associated with poor cardiovascular outcomes and thus provides incremental improvement in early risk stratification.

Response to Letters Regarding Article, “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”

We thank Dr Madias for his insightful comments regarding the limitations of current clinical risk stratification for sudden cardiac death after an acute coronary syndrome and the great clinical need for the development of more sophisticated tools. With over 40 000 days of continuous electrocardiogram monitoring, the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 Trial (MERLIN-TIMI 36) is a rich database for future research, and we are currently investigating whether specific morphological features may identify a subset of more lethal ventricular arrhythmias. We appreciate Dr Madias's suggestions for additional analyses and have embarked on an evaluation of novel electrocardiogram techniques, such as heart …

Letter by Madias Regarding Article, “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”

To the Editor: I read with great interest the important study by Scirica et al,1 published in the August 3, 2010 issue of Circulation , that reported on a possible role of 4- to 7-beat or ≥8-beat nonsustained ventricular tachycardia (NSVT) episodes from ambulatory continuous electrocardiogram recordings (cECG) of 7 days in duration after the randomization of patients with non-ST-segment elevation acute coronary syndrome in predicting 1-year sudden cardiac death (SCD), using the database of Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). This …

Letter by Ayalloore and LeLorier Regarding Article, “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”

To The Editor: The strategy of suppressing ventricular ectopy by pharmaceutical means in the peri-infarct period has been fraught with disappointment and has tinted our view of the approach, as can be seen in the accompanying editorial by Patton.1 The Cardiac Arrhythmia Suppression Trial showed that premature ventricular beat suppression did not prevent sudden cardiac death, but rather increased the risk secondary to the proarrhythmic effects of the antiarrhythmic drugs used.2 Several other trials have reaffirmed these results. In the European Myocardial …

Relationship Between Nonsustained Ventricular Tachycardia After Non–ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death

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. 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. 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.

Clinical Features and Outcomes of Women With Unstable Ischemic Heart Disease

The pathobiological basis of ischemic heart disease and thus the manifestations and response to therapy can differ between women and men. In prior studies, sex-based treatment differences have been observed with the antiischemic ranolazine, with a possibly diminished effect in women. We conducted a prospectively planned analysis of the clinical, biomarker, angiographic, and continuous ECG features and 1-year outcomes of women with unstable ischemic heart disease randomized to ranolazine or placebo in Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). Compared with men (n=4269), women (n=2291) were older with more risk factors (P<0.001). On presentation, women were less likely than men to have significant epicardial coronary artery disease (no stenosis >or=50% on angiography, 19.4% versus 8.6%; P<0.001) or elevated troponin (57.1% versus 68.9%; P<0.001). Yet, women were more likely to have an elevated B-type natriuretic peptide (47.0% versus 40.2%; P<0.001), worse median angina frequency scores (80 versus 100; P<0.001), and an ischemic episode on continuous ECG administered during the first 7 days (22.5% versus 19.3%; P=0.0025). Women and men were at similar adjusted risk for the primary end point of cardiovascular death, myocardial infarction, or recurrent ischemia (adjusted hazard ratio, 1.11; 95% confidence interval, 0.96 to 1.29; P=0.15). Ranolazine was associated with a significant reduction in recurrent ischemia in women (13.0% versus 18.2%; hazard ratio, 0.71; 95% confidence interval, 0.57 to 0.88; P=0.002). Women with a clinical syndrome consistent with unstable ischemic heart disease, despite having less obstructive coronary artery disease, were more likely than men to report anginal episodes and had more recorded ischemic periods on continuous ECG. In this setting, ranolazine may be a particularly useful antiischemic agent in women. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.

B-Type Natriuretic Peptide and the Effect of Ranolazine in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes: Observations From the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary–Thrombolysis In Myocardial Infarction 36) Trial

We designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with acute coronary syndromes (ACS) as part of a randomized, blinded, placebo-controlled trial. Ranolazine is believed to exert anti-ischemic effects by reducing myocardial sodium and calcium overload and consequently ventricular wall stress. BNP increases in response to increased wall stress and is a strong risk indicator in ACS. We measured plasma BNP in all available baseline samples (n = 4,543) among patients with non-ST-segment elevation ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial and followed them for a mean of 343 days. The primary end point was a composite of cardiovascular death, myocardial infarction, and recurrent ischemia. BNP elevation was defined as >80 pg/ml. Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p < 0.0001), cardiovascular death (8.0% vs. 2.1%, p < 0.001), and myocardial infarction (10.6% vs. 5.8%, p < 0.001) at 1 year. In patients with BNP >80 pg/ml, ranolazine reduced the primary end point (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.66 to 0.94, p = 0.009). The effect of ranolazine in patients with BNP >80 pg/ml was directionally similar for recurrent ischemia (HR: 0.78; 95% CI: 0.62 to 0.98; p = 0.04) and cardiovascular death or myocardial infarction (HR: 0.83; 95% CI: 0.66 to 1.05, p = 0.12). There was no detectable effect in those with low BNP (p interaction value = 0.05). Our findings indicate that ranolazine may have enhanced efficacy in high-risk patients with ACS identified by increased BNP. The interaction of biomarkers of hemodynamic stress and the effects of ranolazine warrants additional investigation. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788).

Ischemia Detected on Continuous Electrocardiography After Acute Coronary Syndrome: Observations From the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36) Trial

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).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.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.A total of 6,355 (97%) patients had cECG recordings evaluable for ischemia analysis. Patients with >or=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).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).

Efficacy of Ranolazine in Patients With Chronic Angina: Observations From the Randomized, Double-Blind, Placebo-Controlled MERLIN–TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Segment Elevation Acute Coronary Syndromes) 36 Trial

We aimed to evaluate the efficacy and safety of ranolazine in a larger and more diverse group of patients with angina than previously studied. Ranolazine is an antianginal shown to reduce angina and improve exercise performance in selected patients with early-positive exercise testing and those with frequent angina. We investigated the antianginal effects of ranolazine in the subgroup of patients with prior chronic angina (n = 3,565, 54%) enrolled in the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 36 trial of patients with acute coronary syndrome. Follow-up was a median of 350 days. Patients with prior angina received evidence-based therapy (95% aspirin, 78% statins, 89% beta-blockers, average 2.9 antianginal agents). The primary end point (cardiovascular death, myocardial infarction, recurrent ischemia) was less frequent with ranolazine (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75 to 0.97; p = 0.017), due entirely to a significant reduction in recurrent ischemia (HR: 0.78; 95% CI: 0.67 to 0.91; p = 0.002). Ranolazine also reduced worsening angina (HR: 0.77; 95% CI: 0.59 to 1.00; p = 0.048) and intensification of antianginal therapy (HR: 0.77; 95% CI: 0.64 to 0.92, p = 0.005). Exercise duration at 8 months was greater with ranolazine (514 s vs. 482 s, p = 0.002). Cardiovascular death or myocardial infarction did not differ between treatment groups (HR: 0.97; 95% CI: 0.80 to 1.16; p = 0.71). Symptomatic documented arrhythmias (2.9% vs. 2.9%, p = 0.92) and total mortality (6.2% vs. 6.4%, p = 0.96) were similar with ranolazine or placebo. In this largest study of ranolazine in patients with established coronary artery disease, ranolazine was effective in reducing angina with favorable safety in a substantially broader group of patients with angina than previously studied. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788).

Effects of Ranolazine on Disease-Specific Health Status and Quality of Life Among Patients With Acute Coronary Syndromes

Background— Ranolazine has been shown to reduce myocardial ischemia and symptom severity among selected patients with chronic angina. However, data regarding the effect of ranolazine on health status/quality of life (QOL) are limited. Methods and Results— We performed a prospective QOL analysis alongside the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-elevation acute coronary syndromes (MERLIN)-TIMI 36 trial, a randomized, double-blind, placebo-controlled trial of ranolazine in 6560 patients with non–ST-elevation acute coronary syndromes. Health status/QOL was evaluated at baseline and 4, 8, and 12 months after index hospitalization using the Seattle Angina Questionnaire, Rose dyspnea scale, SF-12, and EuroQol-5D. Health status/QOL scores improved significantly at all follow-up time points for both treatment arms. In the overall population, randomization to ranolazine was associated with minimal 12-month improvements in angina frequency and Seattle Angina Questionnaire-QOL ( P &lt;0.05). In subsequent exploratory analyses, there was a significant interaction between the benefits of ranolazine and anginal status before the index event. Among patients with prior angina (n=3565), treatment with ranolazine was associated with modest benefits across the full range of QOL domains, with the greatest benefits observed in angina frequency (mean effect=3.4; P &lt;0.001) and Seattle Angina Questionnaire-QOL (mean effect=2.7; P &lt;0.001). There were no significant benefits among patients without prior angina, however. Conclusion— Among a broad population of patients with unstable coronary disease, ranolazine had a minimal effect on disease-specific health status and QOL over ≈12 months of follow-up. Posthoc subgroup analysis, however, suggested a modest benefit among the subgroup of patients with angina before their acute coronary syndromes event.