|Year : 2018 | Volume
| Issue : 1 | Page : 17-21
Effect of ranolazine on improvement of left ventricular dysfunction in patients with chronic stable angina: A randomized controlled clinical trial
C R Madhu Prabhu Doss1, Melvin George2, Amrita Jena2, Varsha Srivatsan2, Aruna Sridhar2, VE Dhandapani1
1 Department of Cardiology, SRM Medical College Hospital and Research Centre, Kancheepuram, Tamil Nadu, India
2 Department of Clinical Pharmacology, SRM Medical College Hospital and Research Centre, Kancheepuram, Tamil Nadu, India
|Date of Web Publication||11-Jan-2018|
Dr. Melvin George
Department of Clinical Pharmacology, SRM Medical College Hospital and Research Centre, Kattankulathur, Kancheepuram - 603 203, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Objectives: To study the effect of ranolazine on improvement of left ventricular (LV) dysfunction in comparison to trimetazidine in patients with chronic stable angina (CSA). Ranolazine is an anti-anginal agent that acts on the late inward sodium current and prevents pathologic intracellular calcium accumulation that leads to ischemia, myocardial dysfunction, and electrical instability. Methodology: After screening and obtaining informed consent, 29 patients with CSA who have sustained ST-Elevation Myocardial Infarction more than 12 weeks ago with LV ejection fraction (LVEF) ≤40% in a 2:1 ratio to receive ranolazine 500 mg BD (n = 19) or trimetazidine 35 mg BD (n = 10) were enrolled in the study. The patients were evaluated at the end of 8 weeks for the improvement in LV dysfunction by transthoracic echocardiography. Results: No significant difference was found in the baseline characteristics of the patients between the two groups except the increased body mass index among users of trimetazidine (26.3 ± 5.07 vs. 22.1 ± 3.26, P = 0.03). Study patients receiving ranolazine 500 mg BD for 8 weeks significantly improved the LVEF. No improvement was seen in diastolic function. Ranolazine was well tolerated among the patients. Conclusion: Ranolazine at a dose of 500 mg BD given for 8 weeks helps in improving the LVEF in patients with CSA and is a suitable option than trimetazidine among patients with CSA.
Keywords: Beta blockers, chronic stable angina, coronary artery disease, fatty acid oxidation, left ventricular dysfunction, rennin angiotensin
|How to cite this article:|
Prabhu Doss C R, George M, Jena A, Srivatsan V, Sridhar A, Dhandapani V E. Effect of ranolazine on improvement of left ventricular dysfunction in patients with chronic stable angina: A randomized controlled clinical trial. J Clin Prev Cardiol 2018;7:17-21
|How to cite this URL:|
Prabhu Doss C R, George M, Jena A, Srivatsan V, Sridhar A, Dhandapani V E. Effect of ranolazine on improvement of left ventricular dysfunction in patients with chronic stable angina: A randomized controlled clinical trial. J Clin Prev Cardiol [serial online] 2018 [cited 2021 Jan 16];7:17-21. Available from: https://www.jcpconline.org/text.asp?2018/7/1/17/222922
| Introduction|| |
Coronary artery disease (CAD) continues to be a leading cause of mortality and morbidity worldwide.,,, Patients who have sustained myocardial infarction (MI) develop acute left ventricular (LV) dysfunction. Within 24–48 h of MI, several changes occur in the LV wall including dilatation of the ventricular wall, distortion of ventricular shape, and mural hypertrophy. This results in increased wall stress during the cardiac cycle that activates the mechanoreceptors to produce cardiac hypertrophy. Activation of rennin angiotensin system produces aldosterone-mediated fibrosis that contributes to the remodeling changes., Revascularization through thrombolytic therapy and percutaneous coronary interventions such as angioplasty could significantly improve acute ventricular dysfunction in these patients. However in patients with sustained ventricular dysfunction, the series of changes in the ventricle continue to occur in an indolent manner, resulting in chronic heart failure (HF).
Ranolazine is a drug that has been approved for the treatment of unrelinquished pain in patients with chronic stable angina (CSA) who do not have adequate response to beta blockers and nitrates. The drug blocks the cardiac late sodium current at concentrations that do not inhibit the peak transient current. This unique mechanism of ranolazine reduces angina symptoms by avoiding ischemia-induced sodium overload in cardiac myocytes during ischemia.,, Further, it also inhibits the partially fatty acid oxidation, which results in a shift in substrate metabolism toward glucose during ischemia that may also contribute to reduction in angina symptoms., There have been few studies in the recent years that have attempted to look at the possibility of improvement in the ventricular dysfunction that occurs in these patients. However, there have been contrasting reports from the literature studied till date and the reports are scanty and inconclusive.
We used trimetazidine as control as the drug is a metabolic modulator that could potentially improve LV dysfunction in these patients. Trimetazidine reduces fatty acid oxidation and increases glucose utilization, which restore coupling between glycolysis and carbohydrate oxidation and lead to adenine triphosphate production with less oxygen consumption. It redirects fatty acids toward phospholipids by stimulating membrane phospholipid turnover during ischemia and reperfusion.,, The aim of our study was to assess if short-term treatment with ranolazine for 8 weeks could improve LV systolic and diastolic dysfunction when compared with trimetazidine in patients who have CSA without any coronary event in the last 3 months.
| Methodology|| |
This study was a randomized, single blind, parallel group, active-controlled trial that was conducted in the Department of Cardiology at SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu, India, between January 2014 and August 2015. The protocol was approved by the Institute Ethics Committee of SRM Medical College Hospital and was registered in the Clinical Trial Registry of India CTRI/2014/01/004332 (EFFORT study). A convenience sampling of 30 was used in this pilot study.
Patients diagnosed with CSA visiting the cardiac outpatient department, aged between 18 and 75 years, who have sustained ST-Elevation MI more than 12 weeks ago with LV ejection fraction (EF) ≤40% and were willing to give written informed consent and comply with all study related procedures, were included in the study.
Patients with a history of coronary artery bypass graft or stenting procedure within the last 12 weeks, coexisting end-stage pulmonary or hepatic disease, valvular heart disease, use of study medication in the last 3 months, and those unwilling to comply with study-related procedures were excluded from the study.
All demographic information such as age, sex, previous medical history, clinical features, current drug history, and routine laboratory investigations were recorded. Written informed consent was obtained from all the patients included in the study. Patients were randomized using a computer-generated randomization sequence (Random Allocation software, version 1.0.0, University of Medical Sciences, Iran) to receive ranolazine 500 mg BD or trimetazidine 35 mg BD for 8 weeks. The patients were evaluated at the end of 8 weeks for the improvement in LV dysfunction by transthoracic echocardiography. Sequentially numbered, opaque, sealed, envelopes were used for concealment and were maintained by one of the investigators not involved in patient recruitment. Background medical therapy was given as directed by the treating cardiologist.
The primary objective of the study was to observe the improvement in LV systolic and diastolic function that occurs after 8 weeks of therapy with ranolazine. The secondary objective was to observe improvement in angina symptoms and adverse events (adverse drug reaction) before and after 8 weeks of therapy. In the event of serious adverse event (SAE) occurring in the patient, the study medication would withhold from such patients.
AJ was involved in generating random allocation sequence and maintaining allocation concealment. Enrollment of patients and assignment of interventions to patients were done by MG. MPD was involved in echocardiograph assessment of the study patients in a blinded fashion.
Data were expressed as mean ± standard deviation or median with interquartile range or percentages. The baseline characteristics of the study patients were compared using Student's t-test or Pearson's Chi-squared test. Difference between the ranolazine and trimetazidine groups was compared using Wilcoxon signed-rank test. P < 0.05 was considered statistically significant. Data were analyzed using SPSS for Windows, Version 16.0. (SPSS Inc. Released 2007., IBM, Chicago). No interim analysis was performed.
| Results|| |
A total of 29 patients were enrolled in the study who were randomized in a 2:1 ratio to receive ranolazine 500 mg BD (n = 19) and trimetazidine 35 mg BD (n = 10). There was no restriction on receiving the background medical therapy as directed by the treating cardiologist [Figure 1]. The baseline characteristics of patients such as age, gender, diabetes, hypertension (HTN), smoking, and drinking habits are summarized in [Table 1]. No significant difference was found in the baseline characteristics of the patients between the two groups except the increased body mass index among users of trimetazidine (26.3 ± 5.07 vs. 22.1 ± 3.26, P = 0.03).
The patients were evaluated at the end of 8 weeks for the improvement in LV dysfunction by transthoracic echocardiography [Table 2]. Parameters such as left atrium, LV end diastolic diameter, interventricular septum, LV wall thickness, E-wave deceleration time, E wave, A wave, E/A wave, isovolumic (or isovolumetric) relaxation time, and EF were observed during baseline and follow-up. LV ejection fraction (LVEF) was assessed using Monoplane Simpsons method [Figure 2]a and [Figure 2]b. Significant difference was observed in EF for ranolazine group. Marginal difference was observed in A wave in both the groups.
|Table 2: Effect of ranolazine and trimetazidine on echocardiographic parameters|
Click here to view
|Figure 2: (a and b) Measurement of ejection fraction by monoplane Modified Simpsons Method|
Click here to view
There were no SAEs associated with the study drug. [Table 3] shows the frequency of adverse events observed in both the study groups. Weakness was the most common adverse effect seen among the study patients. Patients receiving trimetazidine had a greater frequency of palpitations when compared to those receiving ranolazine [Table 3].
| Discussion|| |
Our study showed that ranolazine 500 mg BD given for 8 weeks significantly improved the LVEF among the study patients. This is in contrast to other studies which have not shown such observations. In a randomized placebo-controlled Phase II study, 40 patients with chronic CAD who were having angina symptoms on optimal medication and who were not suitable for invasive treatment were randomized to two groups – one group receiving ranolazine 500 mg along with conventional treatment and the other group receiving only conventional treatment. The participants received study medication for 3 months. Patients suffering from chronic CAD taking ranolazine 500 mg for 3 months orally did not show improvement in EF (46.3 ± 3.4 vs. 46.7 ± 2.7) after 3 months of taking the drug. In an open-label study done by Venkataraman et al. in the University of Alabama at Birmingham Medical Center, it was observed that 32 patients with known or suspected CAD and reversible perfusion defects on a clinically indicated stress myocardial perfusion imaging (MPI), receiving ranolazine 500–1000 mg orally twice daily, had no improvement in diastolic and systolic LV synchrony when measured by automated phase analysis of gated single-photon emission computed tomography-MPI. A study was conducted in 22 patients who were enrolled with Doppler echocardiography performed at baseline and at a mean of 2 months after initiation of treatment. The results of the study showed no improvement in both diastolic and systolic functions.
Our study showed that both ranolazine and trimetazidine did not have any change in the diastolic function at the end of 8 weeks of therapy. This is in conflict with other studies that have found significant improvement in diastolic function with ranolazine. For example, a prospective, single-center, open-label, single-group, proof-of-concept study, with blinded end point analysis, done by Singh et al. to assess the effects of ranolazine on diastolic function in patients with moderate-to-severe aortic stenosis and evidence of diastolic dysfunction showed no improvement in diastolic function using peak early diastolic strain rate measured on tagged cardiac magnetic resonance images, after receiving ranolazine for 6 weeks and at 10 weeks (4 weeks after discontinuation).
In contrast, Jacobshagen et al. conducted a prospective, single-center, randomized, double-blind, placebo-controlled proof-of-concept study to examine the effect of ranolazine on diastolic function in patients with HF with preserved EF (HFpEF). Twenty patients with clinical symptoms of HF undergoing cardiac catheterization as part of their routine diagnostic procedure for standard care were randomized to receive ranolazine or placebo in 1.5:1 fashion (12 patients received ranolazine and 8 patients received placebo). The treatment regimen included intravenous infusion of study drug (or placebo) for 24 h, followed by oral treatment for a total of 14 days. It was observed that the LV end-diastolic pressure, pulmonary capillary wedge pressure, and pulmonary artery systolic pressure improved in patients with HFpEF who received ranolazine and no change in diastolic function was assessed by echocardiography (RALI-DHF trial). Hayashida et al. conducted a study to evaluate the effects of ranolazine on regional myocardium of the left ventricle and LV hemodynamics. Angiographic data of 15 patients with previous transmural MI before and after intravenous infusion of ranolazine 200/500 mg/kg body weight were obtained. Regional LV segments were classified into normal (n = 20), ischemic (n = 25), or infracted (n = 45). Examination of regional area fractional shortening, peak filling rate, and segmental wall motion during isovolumic relaxation period was performed. Increase in the regional peak filling rate (1050 ± 410–1133 ± 439 mm/s, P = <0.05) and regional wall lengthening during the isovolumic relaxation period (0.9% ± 4.1%–2.8 ± 5.7% of end-diastolic segmental area, P ≤ 0.05) was observed implying an improvement in the regional diastolic function of the noninfarcted myocardium under chronic ischemic conditions. The sample size of our study was very less with only thirty patients when compared with the above studies which may be a reason for the inadequacy in our data to show the improvement in diastolic function.
In this study, no SAE was observed with ranolazine. Ranolazine was well tolerated among the patients. Weakness was the most common adverse effect seen among the study patients. In a study by Shammas et al., nausea, dizziness, constipation, headache, hypotension, and dyspnea were the most common adverse events among the study patients. SAEs such as nausea and dizziness, arm shaking, back pain, renal abnormality, throat swelling, six patients receiving placebo had chest pain, throat swelling, cough, sinus infection, and chest pain, and rectocele occurred in two patients during washout. In a study done by Cattaneo et al., the most common dose-related adverse events were dizziness, headache, peripheral edema, constipation, and nausea. HTN, cough, and syncope were observed in additional dose-related adverse events.
Our study was not without limitations. As this was a single-centered study, the sample size was relatively small. We could recruit only 29 patients who met the inclusion and exclusion criteria during the study period. The follow-up duration in our study was for a shorter time period of 2 months. Ideally, this should have been extended to 6 months to study the impact of the drug on systolic and diastolic dysfunction.
| Conclusion|| |
Ranolazine when given for a short period of 8 weeks has a modest role in improving systolic dysfunction but has no effect in improving diastolic dysfunction.
We thank all staff of the Department of Cardiology who helped us in conduct of the study. We thank Dr. Sandhiya Selvarajan Assistant Professor, Department of Clinical Pharmacology, JIPMER, Pondicherry for providing us free drug samples.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A. Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 2016;4:256.
Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Flaxman A, et al.
The global burden of ischemic heart disease in 1990 and 2010: The Global Burden of Disease 2010 Study. Circulation 2014;129:1493-501.
Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of coronary heart disease in low-and middle-income countries. Curr Probl Cardiol 2010;35:72-115.
Truffa AA, Newby LK, Melloni C. Extended-release ranolazine: Critical evaluation of its use in stable angina. Vasc Health Risk Manag 2011;7:535-9.
Visser CA. Left ventricular remodelling after myocardial infarction: Importance of residual myocardial viability and ischaemia. Heart 2003;89:1121-2.
Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: A new therapeutic target? Circulation 2004;109:1580-9.
Heeneman S, Sluimer JC, Daemen MJ. Angiotensin-converting enzyme and vascular remodeling. Circ Res 2007;101:441-54.
Pacurari M, Kafoury R, Tchounwou PB, Ndebele K. The renin-angiotensin-aldosterone system in vascular inflammation and remodeling. Int J Inflam 2014;2014:689360.
Weintraub WS, Sadanandan S. Percutaneous coronary intervention in stable patients after acute myocardial infarction. Circulation 2003;108:1292-4.
McMurray JJ, Ezekowitz JA, Lewis BS, Gersh BJ, van Diepen S, Amerena J, et al.
Left ventricular systolic dysfunction, heart failure, and the risk of stroke and systemic embolism in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Circ Heart Fail 2013;6:451-60.
Wimmer NJ, Stone PH. Anti-anginal and anti-ischemic effects of late sodium current inhibition. Cardiovasc Drugs Ther 2013;27:69-77.
Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 2006;113:2462-72.
Hasenfuss G, Maier LS. Mechanism of action of the new anti-ischemia drug ranolazine. Clin Res Cardiol 2008;97:222-6.
Reddy BM, Weintraub HS, Schwartzbard AZ. Ranolazine: A new approach to treating an old problem. Tex Heart Inst J 2010;37:641-7.
Lovelock JD, Monasky MM, Jeong EM, Lardin HA, Liu H, Patel BG, et al.
Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circ Res 2012;110:841-50.
Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart 2005;91:161-5.
Marzilli M. Trimetazidine: A metabolic agent for the treatment of stable angina. Eur Heart J Suppl 2001;3 Supple O:O12-15.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme a thiolase. Circ Res 2000;86:580-8.
Venkataraman R, Chen J, Garcia EV, Belardinelli L, Hage FG, Heo J, et al.
Effect of ranolazine on left ventricular dyssynchrony in patients with coronary artery disease. Am J Cardiol 2012;110:1440-5.
Figueredo VM, Pressman GS, Romero-Corral A, Murdock E, Holderbach P, Morris DL, et al.
Improvement in left ventricular systolic and diastolic performance during ranolazine treatment in patients with stable angina. J Cardiovasc Pharmacol Ther 2011;16:168-72.
Singh A, Steadman CD, Khan JN, Reggiardo G, McCann GP. Effect of late sodium current inhibition on MRI measured diastolic dysfunction in aortic stenosis: A pilot study. BMC Res Notes 2016;9:64.
Jacobshagen C, Belardinelli L, Hasenfuss G, Maier LS. Ranolazine for the treatment of heart failure with preserved ejection fraction: Background, aims, and design of the RALI-DHF study. Clin Cardiol 2011;34:426-32.
Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994;8:741-7.
Shammas NW, Shammas GA, Keyes K, Duske S, Kelly R, Jerin M, et al.
Ranolazine versus placebo in patients with ischemic cardiomyopathy and persistent chest pain or dyspnea despite optimal medical and revascularization therapy: Randomized, double-blind crossover pilot study. Ther Clin Risk Manag 2015;11:469-74.
Bairey Merz CN, Handberg EM, Shufelt CL, Mehta PK, Minissian MB, Wei J, et al.
A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): Impact on angina and myocardial perfusion reserve. Eur Heart J 2016;37:1504-13.
Cattaneo M, Porretta AP, Gallino A. Ranolazine: Drug overview and possible role in primary microvascular angina management. Int J Cardiol 2015;181:376-81.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]