AIMS: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.
MATERIALS AND RESULTS: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).
CONCLUSIONS: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01342029.
<b>BACKGROUND: </b>Incomplete revascularisation is common after percutaneous coronary intervention and is associated with increased mortality and adverse cardiovascular events. We aimed to assess whether adjunctive anti-ischaemic pharmacotherapy with ranolazine would improve the prognosis of patients with incomplete revascularisation after percutaneous coronary intervention.<b>METHODS: </b>We performed this multicentre, randomised, parallel-group, double-blind, placebo-controlled, event-driven trial at 245 centres in 15 countries in Europe, Israel, Russia, and the USA. Patients (aged ≥18 years) with a history of chronic angina with incomplete revascularisation after percutaneous coronary intervention (defined as one or more lesions with ≥50% diameter stenosis in a coronary artery ≥2 mm diameter) were randomly assigned (1:1), via an interactive web-based block randomisation system (block sizes of ten), to receive either twice-daily oral ranolazine 1000 mg or matching placebo. Randomisation was stratified by diabetes history (presence vs absence) and acute coronary syndrome presentation (acute coronary syndrome vs non-acute coronary syndrome). Study investigators, including all research teams, and patients were masked to treatment allocation. The primary endpoint was time to first occurrence of ischaemia-driven revascularisation or ischaemia-driven hospitalisation without revascularisation. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT01442038.<b>FINDINGS: </b>Between Nov 3, 2011, and May 27, 2013, we randomly assigned 2651 patients to receive ranolazine (n=1332) or placebo (n=1319); 2604 (98%) patients comprised the full analysis set. After a median follow-up of 643 days (IQR 575-758), the composite primary endpoint occurred in 345 (26%) patients assigned to ranolazine and 364 (28%) patients assigned to placebo (hazard ratio 0·95, 95% CI 0·82-1·10; p=0·48). Incidence of ischaemia-driven revascularisation and ischaemia-driven hospitalisation did not differ significantly between groups. 189 (14%) patients in the ranolazine group and 137 (11%) patients in the placebo group discontinued study drug because of an adverse event (p=0·04).<b>INTERPRETATION: </b>Ranolazine did not reduce the composite rate of ischaemia-driven revascularisation or hospitalisation without revascularisation in patients with a history of chronic angina who had incomplete revascularisation after percutaneous coronary intervention. Further studies are warranted to establish whether other treatment could be effective in improving the prognosis of high-risk patients in this population.<b>Funding: </b>Gilead Sciences, Menarini.
<b>BACKGROUND: </b>Angina often persists or returns in populations following percutaneous coronary intervention (PCI). We hypothesized that ranolazine would be effective in reducing angina and improving quality of life (QOL) in incomplete revascularization (ICR) post-PCI patients.<b>METHODS AND RESULTS: </b>In RIVER-PCI, 2604 patients with a history of chronic angina who had ICR post-PCI were randomized 1:1 to oral ranolazine versus placebo; QOL analyses included 2389 randomized subjects. Angina and QOL questionnaires were collected at baseline and months 1, 6, and 12. Ranolazine patients were more likely than placebo to discontinue study drug by month 6 (20.4% versus 14.1%, P<0.001) and 12 (27.2% versus 21.3%, P<0.001). Following qualifying index PCI, the primary QOL outcome (Seattle Angina Questionnaire [SAQ] angina frequency score) improved markedly, but similarly, in the ranolazine and placebo groups, respectively, from baseline (67.3±24.5 versus 69.7±24.0, P=0.01) to month 1 (86.6±18.1 versus 85.8±18.5, P=0.27) and month 12 (88.4±17.8 versus 88.5±17.8, P=0.94). SAQ angina frequency repeated measures did not differ in adjusted analysis between groups post baseline (mean difference 1.0; 95% CI -0.2, 2.2; P=0.11). Improvement in SAQ angina frequency was observed with ranolazine at month 6 among diabetics (mean difference 3.3; 95% CI 0.6, 6.1; P=0.02) and those with more angina (baseline SAQ angina frequency ≤60; mean difference 3.4; 95% CI 0.6, 6.2; P=0.02), but was not maintained at month 12.<b>CONCLUSIONS: </b>Despite ICR following PCI, there was no incremental benefit in angina or QOL measures by adding ranolazine in this angiographically-identified population. These measures markedly improved within 1 month of PCI and persisted up to 1 year in both treatment arms.<b>Clinical Trial Registration: </b>URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442038.
Background: Patients with ischemic cardiomyopathy (ICM) may continue to experience persistent chest pain and/or dyspnea despite pharmacologic therapy and revascularization. We hypothesized that ranolazine would reduce anginal symptoms or dyspnea in optimally treated ICM patients.Methods: In this randomized, double-blind, crossover-design pilot study, 28 patients with ICM (ejection fraction less or equal 40%) were included after providing informed consent. A total of 24 patients completed both placebo and ranolazine treatments and were analyzed. All patients were on treatment with a beta blocker, an angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker), and at least one additional antianginal drug. After randomization, patients received up to 1,000 mg ranolazine orally twice a day, as tolerated, versus placebo. The primary end point was change in angina as assessed by the Seattle Angina Questionnaire (SAQ), or in dyspnea as assessed by the Rose Dyspnea Scale (RDS). Change in the RDS and SAQ score from baseline was compared, for ranolazine and placebo, using the Wilcoxon signed rank test or paired t-test. Results: Patients had the following demographic and clinical variables: mean age of 71.5 years; male (82.1%); prior coronary bypass surgery (67.9%); prior coronary percutaneous intervention (85.7%); prior myocardial infarction (82.1%); diabetes (67.9%); and mean ejection fraction of 33.1%. No statistical difference was seen between baseline RDS score and that after placebo or ranolazine (n=20) (P$0.05). There was however, an improvement in anginal frequency (8/10 patients) (P=0.058), quality of life (8/10 patients) (P=0.048), and mean score of all components of the SAQ questionnaire (n=10) (P=0.047) with ranolazine compared with placebo. Conclusion: In optimally treated ICM patients with continued chest pain or dyspnea, ranola-zine possibly had a positive impact on quality of life, a reduction in anginal frequency, and an overall improvement in the mean SAQ component score compared with baseline. Ranolazine did not change the dyspnea score compared with baseline.
INTRODUCTION: The present study examined the effect of ranolazine, which acts via the mechanism of selective inhibition of late INa+, on parameters of left ventricular systolic and diastolic function in patients suffering from angiographically confirmed chronic coronary artery disease, presenting with chronic stable angina.
METHODS: We studied 40 patients (age 67 ± 9 years; 30 men, 10 women) with chronic coronary artery disease who reported angina symptoms on optimal medication and who were not suitable for invasive treatment. Patients were randomized to the ranolazine group (group A, 20 patients taking oral ranolazine 500 mg bid for 3 months) and the control group (group B, 20 patients who did not receive the drug). Left ventricular systolic and diastolic function was assessed echocardiographically at baseline and after the end of the three-month treatment period. Left ventricular ejection fraction by the modified Simpson's method, E and A left ventricular filling velocities, E/A ratio, deceleration time (DT) of E, isovolumic relaxation time (IVRT), E and A waves, and the E/E ratio were measured using 2-dimensional echocardiography, Doppler and tissue Doppler imaging (TDI).
RESULTS: Group A patients demonstrated a clear improvement of their initial angina symptoms. There were no adverse effects from ranolazine requiring withdrawal from the study. There was no statistically significant change in left ventricular systolic function in either group. A statistically significant change was seen in indexes of diastolic function measured using both conventional Doppler and TDI in Group A patients compared with Group B patients after three months' ranolazine treatment period. The changes in left ventricular diastolic function indexes in Group A patients were as follows: E 0.58 ± 0.11 vs. 0.76 ± 0.12 m/s, p<0.001; A 0.71 ± 0.22 vs. 0.83 ± 0.19 m/s, p<0.001; E/A 0.81 ± 0.14 vs. 0.97 ± 0.17, p<0.005; 5.4 ± 0.7 vs. 6.8 ± 0.9 cm/s, p<0.005; 7.2 ± 0.8 vs. 8.3 ± 1.1 cm/s, p<0.005; E/ 10.7 ± 1.1 vs. 11.1 ± 0.8, p=ns; DT 251 ± 14 vs. 226 ± 17 ms, p<0.004; IVRT 95 ± 11 vs. 74 ± 9 ms, p<0.001. Systolic function did not change: EF 46.3 ± 3.4 vs. 46.7 ± 2.7%, p: ns.
CONCLUSIONS: The use of ranolazine in patients suffering from chronic coronary artery disease has a favorable impact on diastolic function parameters. Accordingly, a clinical benefit could be observed due to an improvement in patients' symptoms.
INTRODUCTION: Cardiovascular diseases have become the leading cause of death around the globe and diabetes mellitus (DM) is considered to be a coronary artery disease (CAD) risk equivalent. Ranolazine, an anti anginal drug has been found to reduce Glycated haemoglobin (HbA1c) in diabetes patients with chronic angina. However the effect of another antianginal drug trimetazidine, on glycemic status is not clear.
AIM: To compare the effect of ranolazine and trimetazidine on glycemic status in diabetic patients with CAD.
SETTINGS AND DESIGN: Patients diagnosed with CAD and diabetes mellitus attending Cardiology Out Patient Department (OPD), Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India were recruited for this randomized open label parallel arm trial.
MATERIALS AND METHODS: The study conducted from January-2012 to April-2013 had 47 eligible patients diagnosed with CAD and diabetes mellitus. They were randomized to receive either ranolazine 500 mg BD or trimetazidine 35 mg BD for 12 weeks. HbA1c levels, fasting blood glucose (FBG), lipid profile, QT and QTc intervals were measured at baseline and after 12 weeks.
STATISTICAL ANALYSIS: Unpaired t-test was used to compare the baseline characteristics of between the groups while comparison within the groups were done using Paired t-test. Wilcoxon and Mann Whitney U-tests were used for non parametric data. Graph pad instat version-3 was used for statistical analysis. Values were expressed as mean ± SD. A p < 0.05 was considered statistically significant.
RESULTS: The study could not find any change in HbA1c levels in both ranolazine and trimetazidine groups. The adverse effects reported from patients on ranolazine include angina, constipation, postural hypotension, headache, dizziness, nausea and weakness while patients on trimetazidine complained of constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort, joint pain, etc.
CONCLUSION: In patients with chronic angina and diabetes mellitus Ranolazine 500mg BD and Trimetazidine 35mg BD did not show any effect on HbA1c and fasting blood glucose lebel.
Introduction Ranolazine reduces the Na-dependent calcium overload via inhibition of the late sodium current, improving diastolic tone and oxygen handling during myocardial ischemia. In patients with angina, evidence of myocardial ischemia, but no obstructive coronary artery disease ( CAD), abnormal coronary autoregulation plays a key role. Transthoracic Doppler-derived coronary flow reserve ( CFR) is an index of coronary arterial reactivity and decreases in both microvascular dysfunction and coronary artery stenosis. The aim of this study was to assess the effect of ranolazine on CFR in this group of patient. Methods Fifty-eight (39M, 19F) patients with angina and evidence of myocardial ischemia, but no obstructive CAD, were enrolled in a double-blind, placebo-controlled trial. Participants were assigned to ranolazine (29) or placebo (29) for 8 weeks (up to 500 mg twice a day). CFR was determined as the ratio of hyperemic, induced by intravenous dypiridamole administration, to baseline diastolic coronary flow velocity. CFR was assessed before and after 8-week therapy. Results CFR was successfully performed in all patients. There were no significant differences in baseline characteristics and CFR between ranolazine and placebo group. After 8 weeks CFR significantly increased in ranolazine group (2.54 ± 0.44 vs. 1.91 ± 0.31; P = 0.005) but not in placebo group (1.99 ± 0.32 vs. 1.94 ± 0.29; P = ns). No patient dropped out during 8 weeks therapy. Side effects were similar in both groups. Conclusions Ranolazine is able to improve CFR in these patients. This is probably due to improvement in abnormal coronary autoregulation, both reducing baseline diastolic coronary flow velocity and increasing hyperemic diastolic coronary flow velocity.
OBJETIVOS: Este estudio trata de examinar la eficacia de ranolazina frente a placebo en la frecuencia semanal de pecho y el uso de nitroglicerina sublingual en pacientes con diabetes mellitus tipo 2, la enfermedad arterial coronaria (CAD), y la angina crónica estable que permanecen sintomáticos a pesar del tratamiento con un máximo de 2 antianginal agentes.
ANTECEDENTES: Los pacientes con diabetes tienen más extensa CAD que aquellos sin diabetes, y una alta carga de la angina de pecho. La ranolazina no sólo es eficaz en el tratamiento de la angina de pecho, pero también puede mejorar el control glucémico, lo que proporciona varios beneficios potenciales en este grupo de alto riesgo. Hemos llevado a cabo un ensayo aleatorio para probar el beneficio antianginoso de ranolazina en pacientes con diabetes y la angina de pecho estable.
MÉTODOS: terisa (Tipo 2 Diabetes Evaluación de ranolazina en sujetos con angina crónica estable) fue un ensayo aleatorizado, doble ciego internacional, de ranolazina frente a placebo en pacientes con diabetes, CAD y angina estable tratados con 1 a 2 antianginosos. Después de un estudio doble ciego, de 4 semanas con placebo en los pacientes fueron aleatorizados a 8 semanas de ranolazina doble ciego (dosis objetivo 1000 mg bid) o placebo. Episodios de angina y el uso de nitroglicerina se registraron con entrada diaria en una novela diario electrónico. El resultado primario fue el número promedio semanal de episodios de angina en las últimas 6 semanas del estudio.
RESULTADOS: Un total de 949 pacientes fueron asignados al azar a través de 104 centros en 14 países. La media de edad fue de 64 años, el 61% fueron hombres, con una media de duración de la diabetes fue de 7,5 años y la media de HbA1c basal fue de 7,3%. Electronic captura de datos diario fue del 98% en ambos grupos. Frecuencia de las anginas semanal fue significativamente menor con ranolazina frente a placebo ([intervalo de confianza del 95% (IC): 3.6 a 4.1] 3.8 episodios vs. 4,3 [IC del 95%: 4,0 a 4,5] episodios; p = 0,008), al igual que la sublingual semanal uso de nitroglicerina (1,7 [IC del 95%: 01.06 a 01.09] dosis frente a [IC del 95%: 1,9 a 2,3] 2,1 dosis, p = 0,003). No hubo diferencia en la incidencia de eventos adversos graves entre los grupos.
Conclusiones: En los pacientes con diabetes y la angina crónica a pesar del tratamiento con un máximo de 2 agentes, ranolazina reducida angina y el uso de nitroglicerina sublingual y fue bien tolerado. (Tipo 2 Diabetes Evaluación de ranolazina en sujetos con angina crónica estable [terisa]; NCT01425359).
Los pacientes con angina microvascular (MVA) a menudo tienen la persistencia de los síntomas a pesar del tratamiento completo clásica anti-isquémico. En este estudio, se evaluó el efecto de la ivabradina y ranolazina en pacientes de AMEU. Estamos al azar 46 pacientes con MVA estable (angina de esfuerzo, prueba positiva de esfuerzo [EST], angiografía coronaria normal, reserva de flujo coronario <2,5), que habían síntomas inadecuadamente controlada por la terapia anti-isquémico norma, a la ivabradina (5 mg dos veces al día) , ranolazina (375 mg dos veces al día) o placebo durante 4 semanas. El Seattle Angina Questionnaire (SAQ), escala EuroQoL y EST se evaluaron al inicio y después del tratamiento. La dilatación microvascular coronaria en respuesta a la adenosina y prueba del frío y la función endotelial periférica (por la dilatación mediada por flujo) también fueron evaluados. Ambos fármacos mejoraron artículos SAQ y la escala EuroQoL en comparación con placebo (p <0,01 para todos), con ranolazina que muestran algunos de los efectos más significativos en comparación con ivabradina, en algunos artículos SAQ y la escala EuroQol (p <0,05). Hora de 1 mm depresión del segmento ST y la duración EST se mejoraron por ranolazina en comparación con el placebo. No se observaron efectos sobre la función microvascular coronaria y en la dilatación mediada por flujo con las drogas o el placebo. En conclusión, la ranolazina y ivabradina pueden tener un papel terapéutico en pacientes MVA con un control inadecuado de los síntomas en combinación con la terapia anti-isquémico de costumbre.
OBJETIVO: evaluar si la reducción de la frecuencia cardíaca (FC) tiene efectos beneficiosos sobre la función endotelial en pacientes con diabetes mellitus tipo 2 (DM2).
DISEÑO aleatorios, doble ciego, controlado con placebo.
Lugar: Hospital Universitario.
Pacientes: 66 pacientes con DM2 sin enfermedad cardiovascular manifiesta.
Intervenciones: Los pacientes fueron asignados aleatoriamente a recibir durante 4 semanas, además de su tratamiento habitual, uno de los siguientes tratamientos: atenolol (25 mg dos veces al día), la ivabradina (5 mg dos veces al día) o placebo (1 comprimido dos veces al día).
Principales medidas de resultado: la función endotelial sistémica, evaluados por la dilatación mediada por flujo (FMD); independiente del endotelio vasodilatación, evaluada por nitrato mediada por la dilatación (NMD); la función autonómica cardíaca, evaluado por la variabilidad de recursos humanos (HRV).
RESULTADOS: 61 pacientes completaron el estudio (19, 22 y 20 pacientes en grupos atenolol, ivabradina y placebo, respectivamente). En comparación con la línea base, HR se redujo de manera similar por atenolol (87 ± 13 vs 69 ± 9 bpm) y la ivabradina (86 ± 12 a 71 ± 9 lpm), pero no por placebo (82 ± 10 vs 81 ± 9 lpm) (p < 0,001). Fiebre aftosa mejoró en el seguimiento en el grupo de atenolol (4,8 ± 1,7 vs 6,4 ± 1,9%), pero no en el grupo de ivabradina (5,2 ± 2,5 vs 4,9 ± 2,2%) y en el grupo placebo (4,8 ± 1,5 vs 4,7 ± 1,7 %) (p <0,01). NMD no cambió significativamente en ningún grupo. Parámetros de la VFC no cambiaron en el grupo placebo; que, en cambio, aumentaron constantemente en el atenolol, mientras que un aumento leve en SDNNi sólo se observó en el grupo de ivabradina. Una correlación significativa se encontró en el grupo atenolol entre recursos humanos y cambios de fiebre aftosa (r = -0,48; p = 0,04).
CONCLUSIONES: A pesar de una reducción comparable en recursos humanos, atenolol, pero no ivabradina, la mejora de la fiebre aftosa en los pacientes con DM2 que sugieren que los cambios en recursos humanos son por sí mismos poco probable que mejore significativamente la función endotelial.
The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.
MATERIALS AND RESULTS:
Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).
CONCLUSIONS:
In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.
