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Luiz Belardinelli - One of the best experts on this subject based on the ideXlab platform.
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effect of Ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin
Diabetes Obesity and Metabolism, 2016Co-Authors: Jeremy Pettus, Luiz Belardinelli, Arvinder K Dhalla, Robert H Eckel, Jay S Skyler, B Mcnabb, S Guan, P Jochelson, R H HenryAbstract:Aim To report the results of two phase III trials assessing the efficacy of Ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. Methods In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to Ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving Ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-Ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. Results When added to glimepiride, Ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference −0.11% (95% CI −0.31, 0.1)]. Conclusions Compared with placebo, addition of Ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of Ranolazine added to metformin for glycaemic control can be identified remains unclear.
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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
Clinical Cardiology, 2015Co-Authors: Jorge Antonio Gutierrez, Luiz Belardinelli, Sabina A Murphy, Ewa Karwatowskaprokopczuk, David A Morrow, Ramin Farzanehfar, Gennyne Walker, Benjamin M SciricaAbstract:Over 10 million adults in the United States suffer from angina pectoris, with approximately 500 000 new cases reported annually.1, 2 Traditional antianginal therapy, such as nitrates, β‐blockers, and calcium channel blockers reduce myocardial oxygen demand.3 Ranolazine, a piperazine derivative with anti‐ischemic effects, complements traditional antianginal therapies presumably via inhibition of the late sodium current, thereby minimizing adverse effects associated with intracellular sodium and calcium overload in the setting of myocardial ischemia.4, 5, 6 In patients with chronic stable angina, Ranolazine reduces the frequency of angina and improves exercise performance.5, 7, 8 The addition of Ranolazine to evidence‐based therapy in patients with non–ST‐segment acute coronary syndrome (NSTE ACS) did not reduce rates of the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), or recurrent ischemia in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non‐ST‐Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis In Myocardial Infarction (TIMI) 36 study. Specifically, Ranolazine did not modify the risk of CV death or MI, but did reduce the risk of recurrent ischemia by 13% (P = 0.03).9 The benefit in reducing recurrent ischemia was particularly prominent in the large subgroup of patients with chronic angina preceding NSTE ACS in MERLIN‐TIMI 36, where additionally, Ranolazine improved performance on treadmill or bicycle exercise testing.6 The current analysis focuses again on those patients with a history of chronic angina preceding NSTE ACS and examines the 1‐year incidence of recurrent CV events in patients according to whether they did or did not undergo percutaneous coronary intervention (PCI) within 30 days of presentation for NSTE ACS and whether treatment with Ranolazine modified that relationship.
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effect of Ranolazine monotherapy on glycemic control in subjects with type 2 diabetes
Diabetes Care, 2015Co-Authors: Robert H Eckel, Luiz Belardinelli, Patrick Yue, Arvinder K Dhalla, Robert R Henry, Pamela Wong, Philip Jochelson, Jay S SkylerAbstract:OBJECTIVE Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although Ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, Ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of Ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone. RESEARCH DESIGN AND METHODS The study was conducted worldwide in 465 subjects, with baseline HbA1c of 7–10% (53–86 mmol/mol) and fasting serum glucose of 130–240 mg/dL, randomized to placebo versus Ranolazine. RESULTS Compared with placebo, there was a greater decline in HbA1c at week 24 from baseline (primary end point) in subjects taking Ranolazine (mean difference −0.56% [−6.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjects achieving an HbA1c <7.0% was greater with Ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference −8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference −19 mg/dL; P = 0.0008 vs. placebo). Subjects taking Ranolazine trended toward a greater decrease from baseline in fasting insulin ( P = 0.0507), a greater decrease in fasting glucagon ( P = 0.0003), and a lower postprandial 3-h glucagon area under the curve ( P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated. CONCLUSIONS Compared with placebo, use of Ranolazine monotherapy over 24 weeks, in subjects with type 2 diabetes and inadequate glycemic control on diet and exercise alone, significantly reduced HbA1c and other measures of glycemic control.
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effect of Ranolazine on atrial fibrillation in patients with non st elevation acute coronary syndromes observations from the merlin timi 36 trial
Europace, 2015Co-Authors: Benjamin M Scirica, Luiz Belardinelli, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Jonathan W Waks, Samuel Volo, Mei L Cheng, David A MorrowAbstract:Aims To determine the effect of Ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether Ranolazine reduces the long-term incidence of clinical AF after ACS. Methods and results MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to Ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF ( 0.01–98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to Ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between Ranolazine vs. placebo: clinically insignificant AF (five patients in Ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with Ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with Ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01). Conclusion Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of Ranolazine may be of clinical interest and warrant additional investigation. Clinical trial registration NCT00099788.
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evaluation of Ranolazine in patients with type 2 diabetes mellitus and chronic stable angina results from the terisa randomized clinical trial type 2 diabetes evaluation of Ranolazine in subjects with chronic stable angina
Journal of the American College of Cardiology, 2013Co-Authors: Mikhail N Kosiborod, John A Spertus, Suzanne V Arnold, Darren K Mcguire, Patrick Yue, Ori Benyehuda, Amos Katz, Philip G Jones, Ann Olmsted, Luiz BelardinelliAbstract:Objectives This study sought to examine the efficacy of Ranolazine versus placebo on weekly angina frequency and sublingual nitroglycerin use in subjects with type 2 diabetes mellitus, coronary artery disease (CAD), and chronic stable angina who remain symptomatic despite treatment with up to 2 antianginal agents. Background Patients with diabetes have more extensive CAD than those without diabetes, and a high burden of angina. Ranolazine is not only effective in treating angina but also may improve glycemic control, thus providing several potential benefits in this high-risk group. We conducted a randomized trial to test the antianginal benefit of Ranolazine in patients with diabetes and stable angina. Methods TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina) was an international, randomized, double-blind trial of Ranolazine versus placebo in patients with diabetes, CAD, and stable angina treated with 1 to 2 antianginals. After a single-blind, 4-week placebo run-in, patients were randomized to 8 weeks of double-blind Ranolazine (target dose 1000 mg bid) or placebo. Anginal episodes and nitroglycerin use were recorded with daily entry into a novel electronic diary. Primary outcome was the average weekly number of anginal episodes over the last 6 weeks of the study. Results A total of 949 patients were randomized across 104 centers in 14 countries. Mean age was 64 years, 61% were men, mean diabetes duration was 7.5 years, and mean baseline HbA1c was 7.3%. Electronic diary data capture was 98% in both groups. Weekly angina frequency was significantly lower with Ranolazine versus placebo (3.8 [95% confidence interval (CI): 3.6 to 4.1] episodes vs. 4.3 [95% CI: 4.0 to 4.5] episodes, p = 0.008), as was the weekly sublingual nitroglycerin use (1.7 [95% CI: 1.6 to 1.9] doses vs. 2.1 [95% CI: 1.9 to 2.3] doses, p = 0.003). There was no difference in the incidence of serious adverse events between groups. Conclusions Among patients with diabetes and chronic angina despite treatment with up to 2 agents, Ranolazine reduced angina and sublingual nitroglycerin use and was well tolerated. (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina [TERISA]; NCT01425359)
David A Morrow - One of the best experts on this subject based on the ideXlab platform.
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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
Clinical Cardiology, 2015Co-Authors: Jorge Antonio Gutierrez, Luiz Belardinelli, Sabina A Murphy, Ewa Karwatowskaprokopczuk, David A Morrow, Ramin Farzanehfar, Gennyne Walker, Benjamin M SciricaAbstract:Over 10 million adults in the United States suffer from angina pectoris, with approximately 500 000 new cases reported annually.1, 2 Traditional antianginal therapy, such as nitrates, β‐blockers, and calcium channel blockers reduce myocardial oxygen demand.3 Ranolazine, a piperazine derivative with anti‐ischemic effects, complements traditional antianginal therapies presumably via inhibition of the late sodium current, thereby minimizing adverse effects associated with intracellular sodium and calcium overload in the setting of myocardial ischemia.4, 5, 6 In patients with chronic stable angina, Ranolazine reduces the frequency of angina and improves exercise performance.5, 7, 8 The addition of Ranolazine to evidence‐based therapy in patients with non–ST‐segment acute coronary syndrome (NSTE ACS) did not reduce rates of the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), or recurrent ischemia in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non‐ST‐Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis In Myocardial Infarction (TIMI) 36 study. Specifically, Ranolazine did not modify the risk of CV death or MI, but did reduce the risk of recurrent ischemia by 13% (P = 0.03).9 The benefit in reducing recurrent ischemia was particularly prominent in the large subgroup of patients with chronic angina preceding NSTE ACS in MERLIN‐TIMI 36, where additionally, Ranolazine improved performance on treadmill or bicycle exercise testing.6 The current analysis focuses again on those patients with a history of chronic angina preceding NSTE ACS and examines the 1‐year incidence of recurrent CV events in patients according to whether they did or did not undergo percutaneous coronary intervention (PCI) within 30 days of presentation for NSTE ACS and whether treatment with Ranolazine modified that relationship.
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effect of Ranolazine on atrial fibrillation in patients with non st elevation acute coronary syndromes observations from the merlin timi 36 trial
Europace, 2015Co-Authors: Benjamin M Scirica, Luiz Belardinelli, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Jonathan W Waks, Samuel Volo, Mei L Cheng, David A MorrowAbstract:Aims To determine the effect of Ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether Ranolazine reduces the long-term incidence of clinical AF after ACS. Methods and results MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to Ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF ( 0.01–98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to Ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between Ranolazine vs. placebo: clinically insignificant AF (five patients in Ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with Ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with Ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01). Conclusion Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of Ranolazine may be of clinical interest and warrant additional investigation. Clinical trial registration NCT00099788.
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effect of Ranolazine on a1c and glucose levels in hyperglycemic patients with non st elevation acute coronary syndrome
Diabetes Care, 2010Co-Authors: Jeffrey W Chisholm, Eugene Braunwald, Ewa Karwatowskaprokopczuk, David A Morrow, Arvinder K Dhalla, Allison B Goldfine, Luiz BelardinelliAbstract:OBJECTIVE — We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to Ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris. RESEARCH DESIGN AND METHODS — Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.1 software. RESULTS — In patients with diabetes and A1C of 8 –10% at randomization (n 171), there was an absolute A1C reduction in the Ranolazine group of 1.2% (95% CI 1.4 to 1.0), and the placebo-adjusted (n 182) decrease in A1C by Ranolazine was 0.59% (95% CI 0.99 to0.20,P 0.001). In patients with FPG of 150 – 400 mg/dl at randomization, Ranolazine (n 131) compared with placebo (n 147) reduced FPG by 25.7 mg/dl (95% CI43.3 to8.1,P 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for Ranolazine than placebo (A1C, P 0.046; FPG, P 0.001), indicating that lowering of A1C and FPG by Ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina. CONCLUSIONS — Ranolazine, when added to concurrent antidiabetes treatment, lowers FPG and A1C in patients with cardiovascular disease and poorly controlled diabetes. Diabetes Care 33:1163–1168, 2010
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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
Journal of the American College of Cardiology, 2010Co-Authors: David A Morrow, Benjamin M Scirica, Sabina A Murphy, Marc S Sabatine, James A De Lemos, Petr Jarolim, Pierre Theroux, C Bode, Eugene BraunwaldAbstract:Objectives 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. Background 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. Methods 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. Results Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p 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). Conclusions 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)
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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
Journal of the American College of Cardiology, 2009Co-Authors: Sean R Wilson, Benjamin M Scirica, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Jacqueline Buros, Bernard R Chaitman, David A MorrowAbstract:Objectives We aimed to evaluate the efficacy and safety of Ranolazine in a larger and more diverse group of patients with angina than previously studied. Background 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. Methods 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. Results 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. Conclusions 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 )
Benjamin M Scirica - One of the best experts on this subject based on the ideXlab platform.
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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
Clinical Cardiology, 2015Co-Authors: Jorge Antonio Gutierrez, Luiz Belardinelli, Sabina A Murphy, Ewa Karwatowskaprokopczuk, David A Morrow, Ramin Farzanehfar, Gennyne Walker, Benjamin M SciricaAbstract:Over 10 million adults in the United States suffer from angina pectoris, with approximately 500 000 new cases reported annually.1, 2 Traditional antianginal therapy, such as nitrates, β‐blockers, and calcium channel blockers reduce myocardial oxygen demand.3 Ranolazine, a piperazine derivative with anti‐ischemic effects, complements traditional antianginal therapies presumably via inhibition of the late sodium current, thereby minimizing adverse effects associated with intracellular sodium and calcium overload in the setting of myocardial ischemia.4, 5, 6 In patients with chronic stable angina, Ranolazine reduces the frequency of angina and improves exercise performance.5, 7, 8 The addition of Ranolazine to evidence‐based therapy in patients with non–ST‐segment acute coronary syndrome (NSTE ACS) did not reduce rates of the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), or recurrent ischemia in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non‐ST‐Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis In Myocardial Infarction (TIMI) 36 study. Specifically, Ranolazine did not modify the risk of CV death or MI, but did reduce the risk of recurrent ischemia by 13% (P = 0.03).9 The benefit in reducing recurrent ischemia was particularly prominent in the large subgroup of patients with chronic angina preceding NSTE ACS in MERLIN‐TIMI 36, where additionally, Ranolazine improved performance on treadmill or bicycle exercise testing.6 The current analysis focuses again on those patients with a history of chronic angina preceding NSTE ACS and examines the 1‐year incidence of recurrent CV events in patients according to whether they did or did not undergo percutaneous coronary intervention (PCI) within 30 days of presentation for NSTE ACS and whether treatment with Ranolazine modified that relationship.
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effect of Ranolazine on atrial fibrillation in patients with non st elevation acute coronary syndromes observations from the merlin timi 36 trial
Europace, 2015Co-Authors: Benjamin M Scirica, Luiz Belardinelli, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Jonathan W Waks, Samuel Volo, Mei L Cheng, David A MorrowAbstract:Aims To determine the effect of Ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether Ranolazine reduces the long-term incidence of clinical AF after ACS. Methods and results MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to Ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF ( 0.01–98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to Ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between Ranolazine vs. placebo: clinically insignificant AF (five patients in Ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with Ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with Ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01). Conclusion Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of Ranolazine may be of clinical interest and warrant additional investigation. Clinical trial registration NCT00099788.
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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
Journal of the American College of Cardiology, 2010Co-Authors: David A Morrow, Benjamin M Scirica, Sabina A Murphy, Marc S Sabatine, James A De Lemos, Petr Jarolim, Pierre Theroux, C Bode, Eugene BraunwaldAbstract:Objectives 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. Background 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. Methods 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. Results Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p 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). Conclusions 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)
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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
Journal of the American College of Cardiology, 2009Co-Authors: Sean R Wilson, Benjamin M Scirica, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Jacqueline Buros, Bernard R Chaitman, David A MorrowAbstract:Objectives We aimed to evaluate the efficacy and safety of Ranolazine in a larger and more diverse group of patients with angina than previously studied. Background 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. Methods 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. Results 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. Conclusions 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 )
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evaluation of the glycometabolic effects of Ranolazine in patients with and without diabetes mellitus in the merlin timi 36 randomized controlled trial
Circulation, 2009Co-Authors: David A Morrow, Darren K Mcguire, Benjamin M Scirica, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Carolyn H Mccabe, Eugene BraunwaldAbstract:Background— Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A1c (HbA1c). We designed a prospective evaluation of the effect of Ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial. Methods and Results— We compared HbA1c (percentage) and the time to onset of a ≥1% increase in HbA1c among 4918 patients with acute coronary syndrome randomized to Ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA1c at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, −0.30 versus −0.04; P<0.001). In patients with diabetes mellitus treated with Ranolazine, HbA1c declined from 7.5 to 6.9 (change from baseline, −0.64; P<0.001). Diabetic patients were more likely to achieve an HbA1c <7% at 4 months with Ranolazine compared with placebo (59% versus 49%; P<0.001) and were less likely to have a ≥1% increase in ...
Eugene Braunwald - One of the best experts on this subject based on the ideXlab platform.
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effect of Ranolazine on atrial fibrillation in patients with non st elevation acute coronary syndromes observations from the merlin timi 36 trial
Europace, 2015Co-Authors: Benjamin M Scirica, Luiz Belardinelli, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Jonathan W Waks, Samuel Volo, Mei L Cheng, David A MorrowAbstract:Aims To determine the effect of Ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether Ranolazine reduces the long-term incidence of clinical AF after ACS. Methods and results MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to Ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF ( 0.01–98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to Ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between Ranolazine vs. placebo: clinically insignificant AF (five patients in Ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with Ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with Ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01). Conclusion Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of Ranolazine may be of clinical interest and warrant additional investigation. Clinical trial registration NCT00099788.
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effect of Ranolazine on a1c and glucose levels in hyperglycemic patients with non st elevation acute coronary syndrome
Diabetes Care, 2010Co-Authors: Jeffrey W Chisholm, Eugene Braunwald, Ewa Karwatowskaprokopczuk, David A Morrow, Arvinder K Dhalla, Allison B Goldfine, Luiz BelardinelliAbstract:OBJECTIVE — We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to Ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris. RESEARCH DESIGN AND METHODS — Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.1 software. RESULTS — In patients with diabetes and A1C of 8 –10% at randomization (n 171), there was an absolute A1C reduction in the Ranolazine group of 1.2% (95% CI 1.4 to 1.0), and the placebo-adjusted (n 182) decrease in A1C by Ranolazine was 0.59% (95% CI 0.99 to0.20,P 0.001). In patients with FPG of 150 – 400 mg/dl at randomization, Ranolazine (n 131) compared with placebo (n 147) reduced FPG by 25.7 mg/dl (95% CI43.3 to8.1,P 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for Ranolazine than placebo (A1C, P 0.046; FPG, P 0.001), indicating that lowering of A1C and FPG by Ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina. CONCLUSIONS — Ranolazine, when added to concurrent antidiabetes treatment, lowers FPG and A1C in patients with cardiovascular disease and poorly controlled diabetes. Diabetes Care 33:1163–1168, 2010
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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
Journal of the American College of Cardiology, 2010Co-Authors: David A Morrow, Benjamin M Scirica, Sabina A Murphy, Marc S Sabatine, James A De Lemos, Petr Jarolim, Pierre Theroux, C Bode, Eugene BraunwaldAbstract:Objectives 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. Background 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. Methods 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. Results Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p 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). Conclusions 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)
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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
Journal of the American College of Cardiology, 2009Co-Authors: Sean R Wilson, Benjamin M Scirica, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Jacqueline Buros, Bernard R Chaitman, David A MorrowAbstract:Objectives We aimed to evaluate the efficacy and safety of Ranolazine in a larger and more diverse group of patients with angina than previously studied. Background 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. Methods 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. Results 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. Conclusions 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 )
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evaluation of the glycometabolic effects of Ranolazine in patients with and without diabetes mellitus in the merlin timi 36 randomized controlled trial
Circulation, 2009Co-Authors: David A Morrow, Darren K Mcguire, Benjamin M Scirica, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Carolyn H Mccabe, Eugene BraunwaldAbstract:Background— Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A1c (HbA1c). We designed a prospective evaluation of the effect of Ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial. Methods and Results— We compared HbA1c (percentage) and the time to onset of a ≥1% increase in HbA1c among 4918 patients with acute coronary syndrome randomized to Ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA1c at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, −0.30 versus −0.04; P<0.001). In patients with diabetes mellitus treated with Ranolazine, HbA1c declined from 7.5 to 6.9 (change from baseline, −0.64; P<0.001). Diabetic patients were more likely to achieve an HbA1c <7% at 4 months with Ranolazine compared with placebo (59% versus 49%; P<0.001) and were less likely to have a ≥1% increase in ...
Sabina A Murphy - One of the best experts on this subject based on the ideXlab platform.
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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
Clinical Cardiology, 2015Co-Authors: Jorge Antonio Gutierrez, Luiz Belardinelli, Sabina A Murphy, Ewa Karwatowskaprokopczuk, David A Morrow, Ramin Farzanehfar, Gennyne Walker, Benjamin M SciricaAbstract:Over 10 million adults in the United States suffer from angina pectoris, with approximately 500 000 new cases reported annually.1, 2 Traditional antianginal therapy, such as nitrates, β‐blockers, and calcium channel blockers reduce myocardial oxygen demand.3 Ranolazine, a piperazine derivative with anti‐ischemic effects, complements traditional antianginal therapies presumably via inhibition of the late sodium current, thereby minimizing adverse effects associated with intracellular sodium and calcium overload in the setting of myocardial ischemia.4, 5, 6 In patients with chronic stable angina, Ranolazine reduces the frequency of angina and improves exercise performance.5, 7, 8 The addition of Ranolazine to evidence‐based therapy in patients with non–ST‐segment acute coronary syndrome (NSTE ACS) did not reduce rates of the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), or recurrent ischemia in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non‐ST‐Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis In Myocardial Infarction (TIMI) 36 study. Specifically, Ranolazine did not modify the risk of CV death or MI, but did reduce the risk of recurrent ischemia by 13% (P = 0.03).9 The benefit in reducing recurrent ischemia was particularly prominent in the large subgroup of patients with chronic angina preceding NSTE ACS in MERLIN‐TIMI 36, where additionally, Ranolazine improved performance on treadmill or bicycle exercise testing.6 The current analysis focuses again on those patients with a history of chronic angina preceding NSTE ACS and examines the 1‐year incidence of recurrent CV events in patients according to whether they did or did not undergo percutaneous coronary intervention (PCI) within 30 days of presentation for NSTE ACS and whether treatment with Ranolazine modified that relationship.
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effect of Ranolazine on atrial fibrillation in patients with non st elevation acute coronary syndromes observations from the merlin timi 36 trial
Europace, 2015Co-Authors: Benjamin M Scirica, Luiz Belardinelli, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Jonathan W Waks, Samuel Volo, Mei L Cheng, David A MorrowAbstract:Aims To determine the effect of Ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether Ranolazine reduces the long-term incidence of clinical AF after ACS. Methods and results MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to Ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF ( 0.01–98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to Ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between Ranolazine vs. placebo: clinically insignificant AF (five patients in Ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with Ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with Ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01). Conclusion Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of Ranolazine may be of clinical interest and warrant additional investigation. Clinical trial registration NCT00099788.
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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
Journal of the American College of Cardiology, 2010Co-Authors: David A Morrow, Benjamin M Scirica, Sabina A Murphy, Marc S Sabatine, James A De Lemos, Petr Jarolim, Pierre Theroux, C Bode, Eugene BraunwaldAbstract:Objectives 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. Background 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. Methods 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. Results Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p 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). Conclusions 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)
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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
Journal of the American College of Cardiology, 2009Co-Authors: Sean R Wilson, Benjamin M Scirica, Eugene Braunwald, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Jacqueline Buros, Bernard R Chaitman, David A MorrowAbstract:Objectives We aimed to evaluate the efficacy and safety of Ranolazine in a larger and more diverse group of patients with angina than previously studied. Background 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. Methods 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. Results 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. Conclusions 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 )
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evaluation of the glycometabolic effects of Ranolazine in patients with and without diabetes mellitus in the merlin timi 36 randomized controlled trial
Circulation, 2009Co-Authors: David A Morrow, Darren K Mcguire, Benjamin M Scirica, Sabina A Murphy, Ewa Karwatowskaprokopczuk, Bernard R Chaitman, Carolyn H Mccabe, Eugene BraunwaldAbstract:Background— Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A1c (HbA1c). We designed a prospective evaluation of the effect of Ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial. Methods and Results— We compared HbA1c (percentage) and the time to onset of a ≥1% increase in HbA1c among 4918 patients with acute coronary syndrome randomized to Ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA1c at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, −0.30 versus −0.04; P<0.001). In patients with diabetes mellitus treated with Ranolazine, HbA1c declined from 7.5 to 6.9 (change from baseline, −0.64; P<0.001). Diabetic patients were more likely to achieve an HbA1c <7% at 4 months with Ranolazine compared with placebo (59% versus 49%; P<0.001) and were less likely to have a ≥1% increase in ...
